Cell-free DNA methylation profiles enable early detection of colorectal and gastric cancer.

Colorectal cancer (CRC) and gastric cancer (GC) rank the top five common and lethal cancers worldwide. Early detection can significantly reduce the mortality of CRC and GC. However, current clinical screening methods including invasive endoscopic techniques and noninvasive fecal occult blood test screening tests/fecal immunochemical test have shown low sensitivity or unsatisfactory patient's compliance. Aberrant DNA methylation occurs frequently in tumorigenesis and cell-free DNA (cfDNA) methylation has shown the potential in multi-cancer detection. Herein, we aimed to explore the value of cfDNA methylation in the gastrointestinal cancer detection and develop a noninvasive method for CRC and GC detection. We applied targeted methylation sequencing on a total of 407 plasma samples from patients diagnosed with CRC, GC, and noncancerous gastrointestinal benign diseases (Non-Ca). By analyzing the methylation profiles of 34 CRC, 62 GC and 107 Non-Ca plasma samples in the training set (n=203), we identified 40,110 gastrointestinal cancer-specific markers and 63 tissue of origin (TOO) prediction markers. A new integrated model composed of gastrointestinal cancer detection and TOO prediction for three types of classification of CRC, GC and Non-Ca patients was further developed through logistic regression algorithm and validated in an independent validation set (n=103). The model achieved overall sensitivities of 83% and 81.3% at specificities of 81.5% and 80% for identifying gastrointestinal cancers in the test set and validation set, respectively. The detection sensitivities for GC and CRC were respectively 81.4% and 83.3% in the cohort of the test and validation sets. Among these true positive cancer samples, further TOO prediction showed accuracies of 95.8% and 95.8% for GC patients and accuracies of 86.7% and 93.3% for CRC patients, in test set and validation set, respectively. Collectively, we have identified novel cfDNA methylation biomarkers for CRC and GC detection and shown the promising potential of cfDNA as a noninvasive gastrointestinal cancer detection tool.

Circulating leptin levels in the assessment of Crohn’s disease activity and its relation to nutritional status / Los niveles circulantes de leptina en la evaluación de la actividad de la enfermedad de Crohn y su relación con el estado nutricional

Objective: to evaluate leptin levels and its relation to nutritional status in Crohn’s disease (CD).Methods: the study included 154 CD patients and healthy controls. Leptin level was determined before treatment. Nutrition levels were assessedusing the Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA). Indicators included bodymass index (BMI), mid-arm circumference, the circumference of the upper-arm muscle, triceps skinfold thickness, and circumference of legs.Results: leptin levels differed between CD patients (1,025 ± 874 ng/ml) and controls (18,48 ± 1,222 ng/ml). Significant differences were seenin NRS-2002, PG-SGA scores, BMI and other nutritional indicators. Negative correlations were observed between leptin and NRS-2002, PG-SGAscores, while positive correlations were observed with other nutritional indicators. The receiver operating characteristic (ROC) curve showedassociation between leptin and the diagnosis of CD, suggesting leptin concentration below 803.02 ng/ml as a threshold for CD.Conclusion: dysfunctional leptin regulation may relate to poor nutritional status associated with CD. The leptin level is thus an additional toolfor evaluating CD patients, predicting disease activity and clinical response. Leptin may be a potential target for intervention in CD to improvenutritional status.(AU)

Objetivo: evaluar los niveles de leptina y su relación con el estado nutricional en la enfermedad de Crohn (EC).Métodos: se incluyeron 154 pacientes con EC y controles sanos. El nivel de leptina se determinó antes del tratamiento. La situación nutricionalse evaluó mediante el examen de riesgo nutricional 2002 (NRS-2002) y la Valoración Global Subjetiva Generada por el Paciente (VGS-GP). Losindicadores incluyen el índice de masa corporal (IMC), la circunferencia media del brazo, la circunferencia del músculo superior del brazo, elgrosor del pliegue cutáneo del tríceps y la circunferencia de las piernas.Resultados: los niveles de leptina difirieron entre los pacientes con EC (1.025 ± 874 ng/ml) y los controles (18.48 ± 1.222 ng/ml). Se obser-varon diferencias significativas en NRS-2002, puntajes de VGS-GP, IMC y otros indicadores nutricionales. Se observaron correlaciones negativasentre leptina y NRS-2002, puntuaciones de VGS-GP, mientras que se observaron correlaciones positivas con otros indicadores nutricionales.La curva ROC mostró asociación entre leptina y el diagnóstico de EC, sugiriendo concentraciones de leptina por debajo de 803,02 ng/ml comoumbral para EC.Conclusión: puede relacionarse la alteración en la regulación de la leptina con la peor situación nutricional en enfermos con EC. La leptinapuede ser un objetivo potencial para la intervención en EC a fin de mejorar el estado nutricional.(AU)

Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study.

Background: In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods: In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings: A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Interpretation: Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding: The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.

Targeted modulation of intestinal epithelial regeneration and immune response in ulcerative colitis using dual-targeting bilirubin nanoparticles.

Rationale: The therapeutic benefits of bilirubin in the treatment of ulcerative colitis (UC) are considerable, whereas the underlying mechanism of bilirubin on UC remains unclear remains unexplored. In addition, the weak hydrophilicity and toxicity have limited its translational applications. Methods: We have developed a colon dual-targeting nanoparticle, for orally delivering bilirubin through hydrogel encapsulation of hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGABilirubin). Confocal microscopy and in vivo imaging were used to evaluate the uptake and the targeted property of HA-PLGABilirubin in UC. Immunohistochemistry, immunofluorescence, and transcriptomic analyses were applied to examine the therapeutic effect and potential mechanism of HA-PLGABilirubin in UC. Results: Our results indicated that HA-PLGAbilirubin can significantly enhance the release of bilirubin at simulated intestinal pH and demonstrate higher cellular uptake in inflammatory macrophages. Moreover, in vivo biodistribution studies revealed high uptake and retention of HA-PLGAbilirubin in inflamed colon tissue of UC mouse model, resulting in effective recovery of intestinal morphology and barrier function. Importantly, HA-PLGAbilirubin exerted potent therapeutic efficacy against ulcerative colitis through modulating the intestinal epithelial/stem cells regeneration, and the improvement of angiogenesis and inflammation. Furthermore, genome-wide RNA-seq analysis revealed transcriptional reprogramming of immune response genes in colon tissue upon HA-PLGAbilirubin treatment in UC mouse model. Conclusion: Overall, our work provides an efficient colon targeted drug delivery system to potentiate the treatment of ulcerative colitis via modulating intestinal epithelium regeneration and immune response in ulcerative colitis.

Risks of digestive diseases in long COVID: evidence from a population-based cohort study.

BACKGROUND: In the post-pandemic era, a wide range of COVID-19 sequelae is of growing health concern. However, the risks of digestive diseases in long COVID have not been comprehensively understood. To investigate the long-term risk of digestive diseases among COVID patients. METHODS: In this large-scale retrospective cohort study with up to 2.6 years follow-up (median follow-up: 0.7 years), the COVID-19 group (n = 112,311), the contemporary comparison group (n = 359,671) and the historical comparison group (n = 370,979) predated the COVID-19 outbreak were built using UK Biobank database. Each digestive outcome was defined as the diagnosis 30 days or more after the onset of COVID-19 infection or the index date. Hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting. RESULTS: Compared with the contemporary comparison group, patients with previous COVID-19 infection had higher risks of digestive diseases, including gastrointestinal (GI) dysfunction (HR 1.38 (95% CI 1.26 to 1.51)); peptic ulcer disease (HR 1.23 (1.00 to 1.52)); gastroesophageal reflux disease (GERD) (HR 1.41 (1.30 to 1.53)); gallbladder disease (HR 1.21 (1.06 to 1.38)); severe liver disease (HR 1.35 (1.03 to 1.76)); non-alcoholic liver disease (HR 1.27 (1.09 to 1.47)); and pancreatic disease (HR 1.36 (1.11 to 1.66)). The risks of GERD were increased stepwise with the severity of the acute phase of COVID-19 infection. Even after 1-year follow-up, GERD (HR 1.64 (1.30 to 2.07)) and GI dysfunction (HR 1.35 (1.04 to 1.75)) continued to pose risks to COVID-19 patients. Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of pancreatic diseases (HR 2.57 (1.23 to 5.38)). The results were consistent when the historical cohort was used as the comparison group. CONCLUSIONS: Our study provides insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing digestive diseases. The risks exhibited a stepwise escalation with the severity of COVID-19, were noted in cases of reinfection, and persisted even after 1-year follow-up. This highlights the need to understand the varying risks of digestive outcomes in COVID-19 patients over time, particularly those who experienced reinfection, and develop appropriate follow-up strategies.

Deciphering the Tumor Microenvironment of Colorectal Cancer and Guiding Clinical Treatment With Patient-Derived Organoid Technology: Progress and Challenges.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors of the digestive tract worldwide. Despite notable advancements in CRC treatment, there is an urgent requirement for preclinical model systems capable of accurately predicting drug efficacy in CRC patients, to identify more effective therapeutic options. In recent years, substantial strides have been made in the field of organoid technology, patient-derived organoid models can phenotypically replicate the original intra-tumor and inter-tumor heterogeneity of CRC, reflecting cellular interactions of the tumor microenvironment. Patient-derived organoid models have become an indispensable tool for investigating the pathogenesis of CRC and facilitating translational research. This review focuses on the application of organoid technology in CRC modeling, tumor microenvironment, and guiding clinical treatment, particularly in drug screening and personalized medicine. It also examines the existing challenges encountered in clinical organoid research and provides a prospective outlook on the future development directions of clinical organoid research, encompassing the standardization of organoid culture technology and the application of tissue engineering technology.

Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggests that Rho GTPases play a crucial role in tumorigenesis and metastasis, but their involvement in the tumor microenvironment (TME) and prognosis of hepatocellular carcinoma (HCC) is not well understood. METHODS: We aim to develop a tumor prognosis prediction system called the Rho GTPases-related gene score (RGPRG score) using Rho GTPase signaling genes and further bioinformatic analyses. RESULTS: Our work found that HCC patients with a high RGPRG score had significantly worse survival and increased immunosuppressive cell fractions compared to those with a low RGPRG score. Single-cell cohort analysis revealed an immune-active TME in patients with a low RGPRG score, with strengthened communication from T/NK cells to other cells through MIF signaling networks. Targeting these alterations in TME, the patients with high RGPRG score have worse immunotherapeutic outcomes and decreased survival time in the immunotherapy cohort. Moreover, the RGPRG score was found to be correlated with survival in 27 other cancers. In vitro experiments confirmed that knockdown of the key Rho GTPase-signaling biomarker SFN significantly inhibited HCC cell proliferation, invasion, and migration. CONCLUSIONS: This study provides new insight into the TME features and clinical use of Rho GTPase gene pattern at the bulk-seq and single-cell level, which may contribute to guiding personalized treatment and improving clinical outcome in HCC.

Circulating leptin levels in the assessment of Crohn's disease activity and its relation to nutritional status.

Introduction: Objective: to evaluate leptin levels and its relation to nutritional status in Crohn's disease (CD). Methods: the study included 154 CD patients and healthy controls. Leptin level was determined before treatment. Nutrition levels were assessed using the Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA). Indicators included body mass index (BMI), mid-arm circumference, the circumference of the upper-arm muscle, triceps skinfold thickness, and circumference of legs. Results: leptin levels differed between CD patients (1,025 ± 874 ng/ml) and controls (18,481,222 ng/ml). Significant differences were seen in NRS-2002, PG-SGA scores, BMI and other nutritional indicators. Negative correlations were observed between leptin and NRS-2002, PG-SGA scores, while positive correlations were observed with other nutritional indicators. The receiver operating characteristic (ROC) curve showed association between leptin and the diagnosis of CD, suggesting leptin concentration below 803.02 ng/ml as a threshold for CD. Conclusion: dysfunctional leptin regulation may relate to poor nutritional status associated with CD. The leptin level is thus an additional tool for evaluating CD patients, predicting disease activity and clinical response. Leptin may be a potential target for intervention in CD to improve nutritional status.

Introducción: Objetivo: evaluar los niveles de leptina y su relación con el estado nutricional en la enfermedad de Crohn (EC). Métodos: se incluyeron 154 pacientes con EC y controles sanos. El nivel de leptina se determinó antes del tratamiento. La situación nutricional se evaluó mediante el examen de riesgo nutricional 2002 (NRS-2002) y la Valoración Global Subjetiva Generada por el Paciente (VGS-GP). Los indicadores incluyen el índice de masa corporal (IMC), la circunferencia media del brazo, la circunferencia del músculo superior del brazo, el grosor del pliegue cutáneo del tríceps y la circunferencia de las piernas. Resultados: los niveles de leptina difirieron entre los pacientes con EC (1.025 ± 874 ng/ml) y los controles (18.481.222 ng/ml). Se observaron diferencias significativas en NRS-2002, puntajes de VGS-GP, IMC y otros indicadores nutricionales. Se observaron correlaciones negativas entre leptina y NRS-2002, puntuaciones de VGS-GP, mientras que se observaron correlaciones positivas con otros indicadores nutricionales. La curva ROC mostró asociación entre leptina y el diagnóstico de EC, sugiriendo concentraciones de leptina por debajo de 803,02 ng/ml como umbral para EC. Conclusión: puede relacionarse la alteración en la regulación de la leptina con la peor situación nutricional en enfermos con EC.La leptina puede ser un objetivo potencial para la intervención en EC a fin de mejorar el estado nutricional.

The Overlap Subgroup of Functional Dyspepsia Exhibits More Severely Impaired Gastric and Autonomic Functions.

GOALS: A combination of multiple tests was introduced to noninvasively investigate the differences in pathophysiologies among functional dyspepsia (FD) subgroups, including postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlap. BACKGROUND: It has not been extensively evaluated whether different pathophysiologies are involved in FD subgroups. STUDY: This multicenter study included 364 FD patients fulfilling Rome IV criteria and 47 healthy controls. A combined noninvasive gastric and autonomic function test was performed: The electrogastrogram and electrocardiogram were recorded simultaneously in the fasting state and after a drink test. Symptoms after drinking were recorded using visual analog scale. RESULTS: (1) Compared with HC, FD patients showed a decreased maximum tolerable volume (MTV) ( P <0.01) and percentage of normal gastric slow waves [normal gastric slow waves (%NSW)] ( P <0.01), and increased postdrinking symptoms, anxiety ( P <0.01), and depression ( P <0.01). The drink reduced %NSW in both FD patients and HC; however, the effect was more potent in patients. (2) The PDS and overlap groups displayed a reduced MTV ( P <0.05). The overlap group exhibited a higher symptom score at 30 minutes after drinking, and higher anxiety and depression scores, and a higher sympathovagal ratio than the EPS ( P <0.05 for all) and PDS ( P <0.01 for all). (3) In the PDS subgroup, the MTV, postprandial sympathovagal ratio, and depression were associated with the overall dyspepsia symptom scale (DSS, P =0.034, 0.021, 0.043, respectively). No significant associations were found in the other 2 subgroups. CONCLUSIONS: The combination of multiple tests can detect pathophysiological abnormities in FD patients. Overall, patients with overlap symptoms display more severe pathophysiologies.

Genetically predicted causal associations between periodontitis and psychiatric disorders.

BACKGROUND: Psychiatric disorders have serious harm to individuals' lives with high disease burden. Observational studies reported inconsistent associations between periodontitis and some psychiatric disorders, and the causal correlations between them remain unknown. OBJECTIVE: This study aims to explore the causal associations between periodontitis and psychiatric disorders. METHODS: A series of two-sample Mendelian randomisation (MR) analyses were employed using genome-wide association study summary statistics for periodontitis in adults from Gene-Lifestyle Interactions in Dental Endpoints Consortium and 10 psychiatric disorders from Psychiatric Genomics Consortium. Causal effects were primarily estimated using the inverse-variance weighted (IVW) method. Various sensitivity analyses were also conducted to assess the robustness of our results. FINDINGS: The MR analysis suggested that genetically determined periodontitis was not causally associated with 10 psychiatric disorders (IVW, all p>0.089). Furthermore, the reverse MR analysis revealed that 10 psychiatric disorders had no causal effect on periodontitis (IVW, all p>0.068). We discovered that all the results were consistent in the four MR analytical methods, including the IVW, MR-Egger, weighted median and weighted mode. Besides, we did not identify any heterogeneity or horizontal pleiotropy in the sensitivity analysis. CONCLUSIONS: These results do not support bidirectional causal associations between genetically predicted periodontitis and 10 common psychiatric disorders. Potential confounders might contribute to the previously observed associations. CLINICAL IMPLICATIONS: Our findings might alleviate the concerns of patients with periodontitis or psychiatric disorders. However, further research was warranted to delve into the intricate relationship between dental health and mental illnesses.

The ATF2/miR-3913-5p/CREB5 axis is involved in the cell proliferation and metastasis of colorectal cancer.

Various miRNAs have been shown to participate in the tumor progression and development of colorectal cancer (CRC). However, the role of miR-3913-5p in CRC are yet to be clearly defined. In the present study, we determine that miR-3913-5p is downregulated in CRC cell lines and CRC tissues. Exogenous miR-3913-5p expression weakens the CRC cells growth, migration and invasion. Mechanistically, miR-3913-5p directly targets the 3'UTR of CREB5. Overexpression of CREB5 reverses the suppression of CRC cells proliferation, migration and invasion induced by miR-3913-5p. Furthermore, ATF2 negatively regulates the transcription of miR-3913-5p by binding to its promoter. CREB5 can cooperate with ATF2. CREB5 is required for ATF2 in regulating miR-3913-5p. Finally, inverse correlations can be found between the expressions of miR-3913-5p and CREB5 or ATF2 in CRC tissues. Thus, a plausible mechanism of ATF2/miR-3913-5p/CREB5 axis regulating CRC progression is elucidated. Our findings suggest that miR-3913-5p functions as a tumor suppressor in CRC. ATF2/miR-3913-5p/CREB5 axis might be a potential therapeutic target against CRC progression.

Habitual fish oil use and risk of COVID-19-related outcomes: Evidence from a large scale cohort study and Mendelian randomization analysis.

BACKGROUND & AIMS: Previous findings for the effects of fish oil on COVID-19-related outcomes remain largely inconclusive and controversy persists. Large population-based studies in real-life settings are required to explore the impact of habitual fish oil use on Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, Coronavirus disease 2019 (COVID-19)-related hospitalization and death. To investigate the associations between habitual fish oil use and SARS-CoV-2infection, COVID-19-related outcome. METHODS: Cohort study based on the UK Biobank. 466,572 participants were enrolled. For Mendelian randomization (MR) study, single-nucleotide variants were selected for exposures of fish-oil-derived n-3 PUFAs, including docosapentaenoic acid (DPA). RESULTS: 146,969 (31.5%) participants reported their habitual fish oil use at baseline. Compared with non-fish-oil-users, the hazard ratios for habitual users were 0.97 (95% confidence interval [CI] 0.94 to 0.99) for SARS-CoV-2 infection, 0.92 (95% CI 0.85 to 0.98) for COVID-19-related hospitalization and 0.86 (95% CI 0.75 to 0.98) for COVID-19-related death. MR showed that a higher level of circulating DPA is casually associated with a lower risk of severe COVID-19 (IVW, odds ratio = 0.26, 95% CI 0.08-0.88, P = 0.030). CONCLUSIONS: In this large cohort, we found that habitual fish oil use was significantly associated with lower risks of SARS-CoV-2 infection, hospitalization and death from COVID-19. MR analyses further support a possible causal role of DPA, one of the components of fish oil and valid biomarkers of dietary intake, in reducing the risk of severe COVID-19.

Dissecting shared genetic architecture between obesity and multiple sclerosis.

BACKGROUND: Observational studies have associated obesity with an increased risk of multiple sclerosis (MS). However, the role of genetic factors in their comorbidity remains largely unknown. Our study aimed to investigate the shared genetic architecture underlying obesity and MS. METHODS: By leveraging data from genome-wide association studies, we investigated the genetic correlation of body mass index (BMI) and MS by linkage disequilibrium score regression and genetic covariance analyser. The casualty was identified by bidirectional Mendelian randomisation. Linkage disequilibrium score regression in specifically expressed genes and multimarker analysis of GenoMic annotation was utilised to explore single-nucleotide polymorphism (SNP) enrichment at the tissue and cell-type levels. Shared risk SNPs were derived using cross-trait meta-analyses and Heritability Estimation from Summary Statistics. We explored the potential functional genes using summary-data-based Mendelian randomization (SMR). The expression profiles of the risk gene in tissues were further examined. FINDINGS: We found a significantly positive genetic correlation between BMI and MS, and the causal association of BMI with MS was supported (ß = 0.22, P = 8.03E-05). Cross-trait analysis yielded 39 shared risk SNPs, and the risk gene GGNBP2 was consistently identified in SMR. We observed tissue-specific level SNP heritability enrichment for BMI mainly in brain tissues for MS in immune-related tissues, and cell-type-specific level SNP heritability enrichment in 12 different immune cell types in brain, spleen, lung, and whole blood. The expressions of GGNBP2 were significantly altered in the tissues of patients with obesity or MS compared to those of control subjects. INTERPRETATION: Our study indicates the genetic correlation and shared risk genes between obesity and MS. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics. FUNDING: This work was funded by the National Natural Science Foundation of China (82171698, 82170561, 81300279, and 81741067), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), Natural Science Foundation of Guangdong Province (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Programme of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201803, KJ012019099, KJ012021143, and KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).

Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease.

Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.

Associations of habitual glucosamine use with SARS-CoV-2 infection and hospital admission and death with COVID-19: Evidence from a large population based cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has led to a fundamental number of morbidity and mortality worldwide. Glucosamine was indicated to help prevent and control RNA virus infection preclinically, while its potential therapeutic effects on COVID-19-related outcomes are largely unknown. To assess the association of habitual glucosamine use with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospital admission, and mortality with COVID-19 in a large population based cohort. Participants from UK Biobank were reinvited between June and September 2021 to have SARS-CoV-2 antibody testing. The associations between glucosamine use and the risk of SARS-CoV-2 infection were estimated by logistic regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) for COVID-19-related outcomes were calculated using COX proportional hazards model. Furthermore, we carried out propensity-score matching (PSM) and stratified analyses. At baseline, 42 673 (20.7%) of the 205 704 participants reported as habitual glucosamine users. During median follow-up of 1.67 years, there were 15 299 cases of SARS-CoV-2 infection, 4214 cases of COVID-19 hospital admission, and 1141 cases of COVID-19 mortality. The fully adjusted odds ratio of SARS-CoV-2 infection with glucosamine use was 0.96 (95% CI: 0.92-1.01). The fully adjusted HR were 0.80 (95% CI: 0.74-0.87) for hospital admission, and 0.81 (95% CI: 0.69-0.95) for mortality. The logistic regression and Cox proportional hazard analyses after PSM yielded consistent results. Our study demonstrated that habitual glucosamine use is associated with reduced risks of hospital admission and death with COVID-19, but not the incidence of SARS-CoV-2 infection.

Joint Detection of Serum Vitamin D, Body Mass Index, and Tumor Necrosis Factor Alpha for the Diagnosis of Crohn's Disease.

OBJECTIVE: Vitamin D (VD) deficiency was reported to contribute to the progression of Crohn's disease (CD) and affect the prognosis of CD patients. This study investigated the role of serum VD, body mass index (BMI), and tumor necrosis factor alpha (TNF-α) in the diagnosis of Crohn's disease. METHODS: CD patients (n=76) and healthy subjects (n=76) were enrolled between May 2019 and December 2020. The serum 25-hydroxyvitamin D [25(OH)D] levels, BMI, and TNF-α levels, together with other biochemical parameters, were assessed before treatment. The diagnostic efficacy of the single and joint detection of serum 25(OH)D, BMI, and TNF-α was determined using receiver operating characteristic (ROC) curves. RESULTS: The levels of 25(OH) D, BMI, and nutritional indicators, including hemoglobin, total protein, albumin, and high-density lipoprotein cholesterol, were much lower, and the TNF-α levels were much higher in the CD patients than in the healthy subjects (P<0.05 for all). The areas under the ROC curve for the single detection of 25(OH)D, BMI, and TNF-α were 0.887, 0.896, and 0.838, respectively, with the optimal cutoff values being 20.64 ng/mL, 19.77 kg/m2, and 6.85 fmol/mL, respectively. The diagnostic efficacy of the joint detection of 25(OH)D, BMI, and TNF-α was the highest, with an area under the ROC curve of 0.988 (95%CI: 0.968-1.000). CONCLUSION: The joint detection of 25(OH)D, TNF-α, and BMI showed high sensitivity, specificity, and accuracy in CD diagnosis; thus, it would be effective for the diagnosis of CD in clinical practice.

Identification of shared fatty acid metabolism related signatures in dilated cardiomyopathy and myocardial infarction.

Aim: It is to be elucidated the risk-predictive role of differentially expressed fatty acid metabolism related genes (DE-FRGs) in dilated cardiomyopathy (DCM) and myocardial infarction. Materials & methods: Four gene enrichment analyses defined DE-FRGs' biological functions and pathways. Three strategies were applied to identify risk biomarkers and construct a nomogram. The 4-DE-FRG correlation with immune cell infiltration, drugs, and ceRNA was explored. Results: DE-FRGs were enriched in lipid metabolism. A risk nomogram was established by ACSL1, ALDH2, CYP27A1 and PPARA, demonstrating a good ability for DCM and myocardial infarction prediction. PPARA was positively correlated with adaptive immunocytes. Thirty-five drugs are candidate therapeutic targets. Conclusion: A nomogram and new biological targets for early diagnosis and treatment of DCM and myocardial infarction were provided.

Dilated cardiomyopathy (DCM) and myocardial infarction (MI) are two common types of heart disease. This study investigated the fatty acid metabolism related genes to predict the risk of DCM or MI. Four of them (ACSL1, ALDH2, CYP27A1 and PPARA) were effective in predicting disease risk. Additionally, PPARA was found to be associated with immune cell infiltration, and 35 drugs emerged as potential therapeutic targets for these diseases. This study may provide insights into the early diagnosis and treatment of DCM and MI.

Deep vein thrombosis in a patient with Cronkhite-Canada syndrome: a complex case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare disease characterized by generalized gastrointestinal polyps, ectodermal abnormalities and variable gastrointestinal symptoms. Few cases to date have described complications with deep vein thrombosis (DVT). Here we reported a rare case of CCS concomitant with DVT. The patient's clinical details, endoscopic findings, safety, and efficacy are reported. CASE PRESENTATION: A 58-year-old patient was admitted to our hospital with recurrent diarrhea, overall abnormal appearance, including hyperpigmentation, hair loss and onychodystrophy, and multiple polyps distributed along the gastrointestinal tract except the esophagus. After considerable assessment, the patient was diagnosed with CCS. She was also diagnosed with concurrent DVT, nephrotic syndrome, and infectious enteritis during the course of disease. After treatment with a combination of methylprednisolone, mesalazine, antibiotics, rivaroxaban, and nutritional support during the 24 months of following the patient in this case, the clinical manifestations and endoscopic findings reached complete remission two years after the diagnosis. CONCLUSION: To our knowledge, this study is the first case of CCS complicated with DVT reported in China. Although rare, it is important to consider that DVT may occur after CCS and that it is vital to conduct careful follow-up.

Lack of Causal Associations of Inflammatory Bowel Disease with Parkinson's Disease and Other Neurodegenerative Disorders.

BACKGROUND: Observational studies have indicated associations between inflammatory bowel disease (IBD) and neurodegenerative diseases, including Parkinson's disease (PD). OBJECTIVE: To evaluate the causal associations of IBD with PD and other selected neurodegenerative disorders using updated data. METHODS: Bidirectional two-sample Mendelian randomization studies using genome-wide association studies summary statistics of IBD and PD. RESULTS: We found a lack of evidence for the causal association of IBD on PD (odds ratio [OR], 1.014; 95% confidence interval [CI], 0.967-1.063; P = 0.573). Reverse analysis also indicated no evidence of a causal effect for PD on IBD (OR, 0.978; 95% CI, 0.910-1.052; P = 0.549). The causality between IBD and Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis was unfounded (all P > 0.05). CONCLUSIONS: The updated analyses provide no clear evidence for causal associations of IBD with PD or the other three neurodegenerative diseases. Potential confounders might contribute to the previously observed associations, and further investigations are warranted. © 2023 International Parkinson and Movement Disorder Society.