Background/Aims: The association between caffeine intake and constipation remains inconclusive. This study aims to investigate whether caffeine intake is associated with constipation. Methods: This cross-sectional study included 13 941 adults from the 2005-2010 National Health and Nutrition Examination Survey. The weighted logistic regression analyses were exerted to evaluate the association between caffeine intake and constipation. Besides, stratified analyses and interaction tests were conducted to determine the potential modifying factors. Results: After adjusting for confounders, increased caffeine intake by 100 mg was not associated with constipation, as defined by stool frequency (OR, 1.01; 95% CI, 0.94-1.10) or stool consistency (OR, 1.01; 95% CI, 0.98-1.05). Subgroup analyses showed that cholesterol intake modified the relationship between increased caffeine by 100 mg and stool frequency-defined constipation (P for interaction = 0.037). Each 100 mg increase in caffeine intake was associated with a 20% decreased risk of constipation defined by stool frequency in participants who consumed high cholesterol (OR, 0.80; 95% CI, 0.64-1.00), but no association in the other 2 cholesterol level groups. Furthermore, the association between caffeine intake and stool consistency-defined constipation was not found in different cholesterol groups. Conclusions Caffeine consumption is not associated with stool frequency or consistency-defined constipation. Nevertheless, increased caffeine intake may decrease the risk of constipation (defined by stool frequency) among participants in the high-cholesterol intake group.

Background/Aims: The association between caffeine intake and constipation remains inconclusive. This study aims to investigate whether caffeine intake is associated with constipation. Methods: This cross-sectional study included 13 941 adults from the 2005-2010 National Health and Nutrition Examination Survey. The weighted logistic regression analyses were exerted to evaluate the association between caffeine intake and constipation. Besides, stratified analyses and interaction tests were conducted to determine the potential modifying factors. Results: After adjusting for confounders, increased caffeine intake by 100 mg was not associated with constipation, as defined by stool frequency (OR, 1.01; 95% CI, 0.94-1.10) or stool consistency (OR, 1.01; 95% CI, 0.98-1.05). Subgroup analyses showed that cholesterol intake modified the relationship between increased caffeine by 100 mg and stool frequency-defined constipation (P for interaction = 0.037). Each 100 mg increase in caffeine intake was associated with a 20% decreased risk of constipation defined by stool frequency in participants who consumed high cholesterol (OR, 0.80; 95% CI, 0.64-1.00), but no association in the other 2 cholesterol level groups. Furthermore, the association between caffeine intake and stool consistency-defined constipation was not found in different cholesterol groups. Conclusions Caffeine consumption is not associated with stool frequency or consistency-defined constipation. Nevertheless, increased caffeine intake may decrease the risk of constipation (defined by stool frequency) among participants in the high-cholesterol intake group.

Background/Aims: The association between caffeine intake and constipation remains inconclusive. This study aims to investigate whether caffeine intake is associated with constipation. Methods: This cross-sectional study included 13 941 adults from the 2005-2010 National Health and Nutrition Examination Survey. The weighted logistic regression analyses were exerted to evaluate the association between caffeine intake and constipation. Besides, stratified analyses and interaction tests were conducted to determine the potential modifying factors. Results: After adjusting for confounders, increased caffeine intake by 100 mg was not associated with constipation, as defined by stool frequency (OR, 1.01; 95% CI, 0.94-1.10) or stool consistency (OR, 1.01; 95% CI, 0.98-1.05). Subgroup analyses showed that cholesterol intake modified the relationship between increased caffeine by 100 mg and stool frequency-defined constipation (P for interaction = 0.037). Each 100 mg increase in caffeine intake was associated with a 20% decreased risk of constipation defined by stool frequency in participants who consumed high cholesterol (OR, 0.80; 95% CI, 0.64-1.00), but no association in the other 2 cholesterol level groups. Furthermore, the association between caffeine intake and stool consistency-defined constipation was not found in different cholesterol groups. Conclusions Caffeine consumption is not associated with stool frequency or consistency-defined constipation. Nevertheless, increased caffeine intake may decrease the risk of constipation (defined by stool frequency) among participants in the high-cholesterol intake group.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by radical surgery has been a common practice for patients with locally advanced rectal cancer, but the response rate varies among patients. This study aimed to develop a ResNet-Vision Transformer based magnetic resonance imaging (MRI)-endoscopy fusion model to precisely predict treatment response and provide personalized treatment. METHODS: In this multicenter study, 366 eligible patients who had undergone neoadjuvant chemoradiotherapy followed by radical surgery at eight Chinese tertiary hospitals between January 2017 and June 2024 were recruited, with 2928 pretreatment colonic endoscopic images and 366 pelvic MRI images. An MRI-endoscopy fusion model was constructed based on the ResNet backbone and Transformer network using pretreatment MRI and endoscopic images. Treatment response was defined as good response or non-good response based on the tumor regression grade. The Delong test and the Hanley-McNeil test were utilized to compare prediction performance among different models and different subgroups, respectively. The predictive performance of the MRI-endoscopy fusion model was comprehensively validated in the test sets and was further compared to that of the single-modal MRI model and single-modal endoscopy model. RESULTS: The MRI-endoscopy fusion model demonstrated favorable prediction performance. In the internal validation set, the area under the curve (AUC) and accuracy were 0.852 (95% confidence interval [CI]: 0.744-0.940) and 0.737 (95% CI: 0.712-0.844), respectively. Moreover, the AUC and accuracy reached 0.769 (95% CI: 0.678-0.861) and 0.729 (95% CI: 0.628-0.821), respectively, in the external test set. In addition, the MRI-endoscopy fusion model outperformed the single-modal MRI model (AUC: 0.692 [95% CI: 0.609-0.783], accuracy: 0.659 [95% CI: 0.565-0.775]) and the single-modal endoscopy model (AUC: 0.720 [95% CI: 0.617-0.823], accuracy: 0.713 [95% CI: 0.612-0.809]) in the external test set. CONCLUSION The MRI-endoscopy fusion model based on ResNet-Vision Transformer achieved favorable performance in predicting treatment response to neoadjuvant chemoradiotherapy and holds tremendous potential for enabling personalized treatment regimens for locally advanced rectal cancer patients.
Humans ; Rectal Neoplasms/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Male ; Female ; Middle Aged ; Neoadjuvant Therapy/methods* ; Aged ; Adult ; Chemoradiotherapy/methods* ; Endoscopy/methods* ; Treatment Outcome

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Objective To investigate the expression,synergistic relationship and clinical significance of alcohol de-hydrogenase(ADH1A)and vascular endothelial growth factor-A(VEGFA)in hepatocellular carcinoma(HCC).Methods The expression and correlation of ADH1A and VEGFA in HCC and adjacent normal tissues were ana-lyzed by GEPIA.TCGA and GSEA were used to analyze the pathway of ADH1A in HCC.The clinical and patho-logical data of 84 patients with HCC were collected,and 54 patients with paracancer normal tissue samples were se-lected as controls to analyze the correlation between ADH1A and VEGFA and clinicopathological parameters of HCC.Immunohistochemistry was used to detect the protein expression of ADH1A and VEGFA in cases and con-trols,and the correlation between the expression of ADH1A and VEGFA and the clinical progression and prognosis of patients with HCC was analyzed based on clinical pathological parameters and Kaplan-Meier.Results Bioinfor-matics analysis found that ADH1A was low-expressed in HCC and VEGFA was highly expressed in HCC,and there was a negative correlation between the two(P<0.001);immunohistochemical detection results showed that the expression of ADH1A in HCC tissue was lower than that in normal tissue adjacent to cancer(P<0.01)while the expression rate of VEGFA in HCC tissue was significantly higher than that of normal tissue adjacent to cancer(P<0.01);The recurrence rate of vascular thrombus and HCC patients in HCC group with high expression of ADH1A was lower(P<0.05).The proportion of tumor diameter>5 cm,high TNM stage,microsatellite and G2-G3 dif-ferentiation in HCC tissues in VEGFA high expression group was higher(P<0.05).Kaplan-Meier survival analy-sis showed that patients with high ADH1A expression and low VEGFA expression had a higher five-year survival rate.Conclusion Low expression of ADH1A and high expression of VEGFA in tumor tissues of patients with HCC indicate tumor progression and can be used as one of the prognostic evaluation indicators for patients with HCC.

ObjectiveTo explore the risk of different levels of pre-pregnancy obesity on trimester-specific thyroid dysfunction. MethodsQuestionnaire information， blood samples， and urine samples from a 2017 pregnancy cohort study in Shanghai， China were collected. A total of 2 455 pregnant women were included in the analysis. Pre-pregnancy BMI was calculated based on the height and self-reported pre-pregnancy weight. Serum TSH， total thyroxine （TT4）， free thyroxine （FT4）， total triiodothyronine （TT3）， free triiodothyronine （FT3）， thyroid globulin antibody（TgAb）， and Thyroid peroxidase antibody （TPOAb） were measured using the electrochemiluminescence method. Urine iodine levels were measured using the acid digestion method. Levels of thyroid function indexes of pregnant women with different degrees of obesity during pre-pregnancy were compared， and trimester-specific thyroid dysfunction was evaluated according to the reference range of trimester-specific thyroid hormone established by this cohort. Multivariate logistic regressions analysis was used to assess the correlation between pre-pregnancy obesity and trimester-specific thyroid dysfunction. ResultsAs the degree of obesity increased， maternal levels of FT3 and TT3 gradually increased during pregnancy （P<0.001， P=0.001）， while FT4 levels gradually decreased （P=0.001）. Multivariate logistic regression analysis showed that compared with the normal weight group， pregnant women who were overweight or obesity before pregnancy had a significantly higher risk of hypothyroxinemia （OR=3.85， 95%CI： 2.08‒7.14， P<0.001） and high TT3 （OR=2.78， 95%CI： 1.45‒5.26， P=0.002） during pregnancy. ConclusionPre-pregnancy overweight or obesity can increase the risk of thyroid dysfunction during pregnancy.

We reported a 26-year-old male who was diagnosed with apical hypertrophic cardiomyopathy with left ventricular aneurysm. The location of the hypertrophic myocardium and the extent of resection were accurately assessed preoperatively using 3D modeling and printing technology. Myectomy was performed via transapical approach, and the intraoperative exploration was consistent with the description of the preoperative 3D modeling. The patient underwent the surgery successfully without any complications during the hospitalization, and the cardiopulmonary bypass time was 117 min, the aortic cross-clamping time was 57 min, and the hospital stay time was 7 d. The postoperative echocardiography demonstrated left ventricular cavity flow patency. This case provides a reference for the management of patients with apical hypertrophic cardiomyopathy.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective: To investigate the role and mechanism of Sigirr deletion in chronic kidney disease complicated with renal interstitial fibrosis (CKD⁃RIF) in mice. Methods: polymerase chain reaction (PCR) was used for identification of gene types of mice. Mice were continuously fed with the foods containing 0. 2% adenine for 12 weeks to establish the CKD⁃RIF models. Then , serum was collected to detect levels of creatinine and nitrogen when mice were killed. H&E staining was used to analyze the pathological changes of kidney tissues. Masson staining was used to observe the degree of renal fibrosis. Immunohistochemistry was used to detect the changes of the interest proteins , such as IL⁃1β , MyD88 , activated NF⁃κB , TGF⁃ β1 , E ⁃cadherin and Vimentin. Results: Serum creatinines and urea nitrogens of mice fed with high adenine (CKD⁃RIF groups) significantly increased , compared with those of the control groups. H&E and Masson staining results showed that there were more infiltrated inflammatory cells and more critical collagen fiber deposition in the renal tissues of the Sigirr - / - mice with CKD⁃RIF. Western blot and Immunohistochemical analysis showed that the expression of IL⁃1β and its downstream MyD88 increased , and the level of phosphorylated NF⁃κB (p⁃P65) significantly increased in the renal tissues of CKD⁃RIF mice compared with the controls. And upregulation of these proteins in renal tissues of Sigirr - / - mice with CKD⁃RIF was more obvious than that of the CKD⁃RIF Sigirr + / + mice. TGF⁃ β1 , as a key cytokine involved in renal interstitial fibrosis , significantly increased ,followed by the increase of vimentin , as well as the decrease of E ⁃cadherin . The results of vimentin and cadherin E detected by Western blot were consistent with those of immunohistochemistry , and α ⁃SMA also increased significantly. Conclusion Adenine diet successfully induces CKD⁃RIF mice models. Sigirr deletion is beneficial to activation of the IL⁃1β mediating NF⁃κB signal pathway ,which promotes TGF⁃ β1 expression in the renal interstitiums to induce renal interstitial fibrosis.