Objective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test .Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.

Objective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test .Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.

Based on the theoretical framework of "grease-turbidity-heat toxin"， this paper elucidates the patholo-gical evolution pattern underlying the alternation between active and remission phases of inflammatory bowel disease （IBD）. It is proposed that the active phase of IBD represents a progressive and explosive process characterized by internal accumulation of grease turbidity， constraint transforming into heat， and exuberant heat generating toxin. During the remission phase， the pathogenic process manifests as subsidence of heat toxin， depletion of qi and yin， latent retention of residual turbidity， and a state of coexistence between deficiency of healthy qi and lingering pathogenic factors. Accordingly， a staged therapeutic strategy with dynamic intervention and targeted modulation has been established. During the active phase， treatment follows the sequential principle of unblocking， clearing， and resolving pathogenic factors. In the early stage， the therapeutic approach focuses on regulating qi movement， fortifying the spleen， and resolving turbidity， using Tongxie Essential Formula （痛泻要方） and Shenling Baizhu Powder （参苓白术散） to regulate qi and fortify spleen. In the middle stage， the strategy emphasizes clearing heat， eliminating dampness， and dispersing pathogenic accumulation through downward and outward pathways， and Gegen Qinlian Decoction （葛根芩连汤） combined with Banxia Xiexin Decoction （半夏泻心汤） is used to clear and resolve damp-heat. In the late stage， treatment aims to resolve toxin， restrain sore， cool blood， and stabilize collaterals， using Baitouweng Decoction （白头翁汤）， Shaoyao Decoction （芍药汤）， and Xijiao Dihuang Decoction （犀角地黄汤） to eliminate toxins and cool blood. During the remission phase， the principle of reinforcing， consolidating， and penetrating is adopted to restore internal balance and clear the source， using Sishen Pills （四神丸） and Sijunzi Decoction （四君子汤） to reinforce healthy qi and venting pathogens.

Based on the theory of Zi Wu Liu Zhu （子午流注， the ebb and flow of midnight and midday） and the clinical characteristics of diarrhea-predominant irritable bowel syndrome （IBS-D） that its symptoms mainly occur during chou （丑） period （01：00—03：00）， mao （卯） period （5：00—7：00）， and si （巳） period （9：00—11：00）， this paper proposes a temporal pathogenesis chain of "liver constraint during chou period， intestinal stagnation during mao period， and spleen deficiency during si period". Within this chain， liver constraint serves as the initiating factor， and intestinal stagnation manifests as the branch， while spleen deficiency constitutes the root of the disease. Accordingly， a chronotherapeutic principle of "soothing the liver， regulating the intestines， and fortifying the spleen" is proposed， establishing a corresponding time-based syndrome differentiation and treatment system. During chou period， the treatment should focus on soothing the liver to relieve constraint and calming the mind to tranquilize the spirit， thereby blocking the mechanism of liver constraint overacting on the spleen. During mao period， the focus is regulating qi to resolve dampness and harmonizing the intestine to alleviate the branch symptoms of morning abdominal pain and diarrhea. During si period， the suggested method is fortifying the spleen and supplementing qi to drain dampness and stop diarrhea， thereby restoring the pivot of spleen-stomach transportation and transformation. These methods are complemented by strategies to optimize medication compliance， thereby providing a new chronotherapeutic approach for clinical diagnosis and treatment of IBS-D.

Based on the theoretical framework of "grease-turbidity-heat toxin"， this paper elucidates the patholo-gical evolution pattern underlying the alternation between active and remission phases of inflammatory bowel disease （IBD）. It is proposed that the active phase of IBD represents a progressive and explosive process characterized by internal accumulation of grease turbidity， constraint transforming into heat， and exuberant heat generating toxin. During the remission phase， the pathogenic process manifests as subsidence of heat toxin， depletion of qi and yin， latent retention of residual turbidity， and a state of coexistence between deficiency of healthy qi and lingering pathogenic factors. Accordingly， a staged therapeutic strategy with dynamic intervention and targeted modulation has been established. During the active phase， treatment follows the sequential principle of unblocking， clearing， and resolving pathogenic factors. In the early stage， the therapeutic approach focuses on regulating qi movement， fortifying the spleen， and resolving turbidity， using Tongxie Essential Formula （痛泻要方） and Shenling Baizhu Powder （参苓白术散） to regulate qi and fortify spleen. In the middle stage， the strategy emphasizes clearing heat， eliminating dampness， and dispersing pathogenic accumulation through downward and outward pathways， and Gegen Qinlian Decoction （葛根芩连汤） combined with Banxia Xiexin Decoction （半夏泻心汤） is used to clear and resolve damp-heat. In the late stage， treatment aims to resolve toxin， restrain sore， cool blood， and stabilize collaterals， using Baitouweng Decoction （白头翁汤）， Shaoyao Decoction （芍药汤）， and Xijiao Dihuang Decoction （犀角地黄汤） to eliminate toxins and cool blood. During the remission phase， the principle of reinforcing， consolidating， and penetrating is adopted to restore internal balance and clear the source， using Sishen Pills （四神丸） and Sijunzi Decoction （四君子汤） to reinforce healthy qi and venting pathogens.

Objective: To explore the association between sleep quality and dry eye symptoms in adolescents,so as to provide the evidence for reducing the prevalence of dry eye symptoms. Methods: The study population was adolescents aged 12-24 years from the Psychology and Behavior Investigation of Chinese Residents (PBICR) survey, which was conducted from 20 June to 31 August 2022. A stratified random sampling and quota sampling method was used to select 6 456 adolescents within mainland China. The Ocular Surface Disease Index (OSDI) and Brief version of the Pittsburgh Sleep Quality Index (B-PSQI) were used to assess dry eye symptoms and sleep quality. Multiple Logistic regression model was used to explore the relationship between sleep quality and dry eye symptoms in adolescents. The influence of gender on the association was explored by using interaction terms. Results: A total of 2 815 adolescents reported having dry eye symptoms, with a prevalence of 43.6%. Logistic regression analysis results showed an increased risk of exacerbation of dry eye symptoms in adolescents with poor sleep quality. The OR (95% CI ) for mild, moderate, and severe dry eye symptoms groups were 1.39(1.16-1.67), 1.52(1.28-1.81), and 2.35(2.02-2.72), respectively, compared with the ocularly normal group ( P <0.05). There was a significant interaction between sleep quality and gender on dry eye symptoms in adolescents ( P <0.01). Conclusions Sleep quality is associated with dry eye symptoms in adolescents, and those with poor sleep quality have a higher risk of dry eye symptoms. The effect of sleep quality on dry eye symptoms is greater in boys.

Objective To investigate the mechanism by which angiotensin Ⅱ type 1 receptor autoantibody(AT1-AA)promotes phenotypic switch of vascular smooth muscle cells(VSMCs)and vascular fibrosis through abnormal expression of circadian clock protein BMAL1.Methods Twelve male SD rats(6～8 weeks old,weighing 180～220 g)were randomly divided into(n=6)a control group and an AT1-AA-positive group[established by active immunization of SD rats with AT1R extracellular loop Ⅱ peptide(AT1R-ECLⅡ)].HE and Masson stainings were used to observe structural changes and fibrosis in the thoracic aorta(n=3).Western blotting was performed to detect the expression of Collagen I,phenotypic switch-related proteins(SM22,α-SMA,OPN and MMP2)in vascular tissues and primary VSMCs(n=4),as well as the expression of BMAL1 at CT0,CT4,CT8,CT12,CT16,and CT20.Transwell and scratch assays were used to assess the proliferation and migration of VSMCs(n=3).si-RNA was employed to knock down Bmal1,followed by detection of BMAL1,Collagen I,and phenotypic conversion-related protein expression(n=3).Additionally,AT1-AA-positive AT1R-knockout(AT1R-KO)rats were constructed to measure BMAL1 expression in thoracic aortic tissues(n=4).Results The AT1-AA-positive rats had significantly thickened thoracic aortic vessel wall[(140±9)%vs(120±5)%,P<0.05],badly arranged VSMCs,obvious blue Masson staining,and up-regulated Collagen I expression(P<0.05).In the thoracic aorta of AT1-AA-positive rats and AT1-AA-treated VSMCs,the expression of contractile phenotype-related proteins(α-SMA,SM22)was decreased(P<0.05),while the expression of synthetic phenotype-related proteins(OPN,MMP2)was increased(P<0.05).AT1-AA enhanced the scratch healing ability and migration ability of VSMCs.Furthermore,both mRNA and protein levels of Bmal1 were significantly up-regulated at CT12(P<0.05),and the rhythmicity of Bmal1 was lost.Knockdown of Bmal1 partially ameliorated AT1-AA-induced phenotypic switch of VSMCs.Compared with AT1-AA-positive WT rats,AT1-AA-positive AT1R-KO rats showed significantly reduced BMAL1 expression in the thoracic aorta(1.35±0.06 vs 0.86±0.07,P<0.001).At the cellular level,AT1-AA-induced phenotypic switch and high Collagen I expression in VSMCs were partially improved in AT1R-KO VSMCs.Conclusion AT1-AA promotes VSMCs phenotypic conversion and vascular fibrosis through the AT1R-Bmal1 axis.

ObjectiveTo evaluate the effectiveness of stone needle thermocompression and massage compared to flurbiprofen gel patch in relieving chronic musculoskeletal pain in the shoulder and back， and to explore the potential mediating mechanism through muscle elasticity. MethodsA total of 120 patients with chronic musculoskeletal pain in the shoulder and back were randomly assigned to either stone needle group or flurbiprofen group， with 60 patients in each. The stone needle group received stone needle thermocompression and massage for 30 minutes， three times per week； the flurbiprofen group received flurbiprofen gel patch twice daily. Both groups were treated for 2 weeks. Pain improvement， as the primary outcome， was assessed using the Global Pain Scale （GPS） at baseline， after 2 weeks of treatment， and again 2 weeks post-treatment. To explore potential mechanisms， a mediator analysis was conducted by measuring changes in superficial and deep muscle elasticity using musculoskeletal ultrasound at baseline and after the 2-week treatment period. ResultsThe stone needle group showed significantly greater pain relief than the flurbiprofen group 2 weeks post-treatment. After adjusting for confounders related to pain duration， the between-group mean difference was -8.8 ［95% CI （-18.2， -0.7）， P＜0.05］. Part of the therapeutic effect was mediated by changes in deep muscle elasticity， with a mediation effect size of -1.5 ［95% CI （-2.0， -0.9）， P = 0.024］， accounting for 17.9% of the total effect. ConclusionStone needle thermocompression and massage can effectively relieve chronic musculoskeletal pain in the shoulder and back， partly through a mediating effect of improved deep muscle elasticity.

Objective:To investigate the interactive effects of loss of the only child and childhood trauma on brain structure, function, and structure-function coupling, and to analyze their association with clinical symptom.Methods:A total of 112 parents who lost their only child and participated in the psychological aid project organized by Local Civil Affairs Department in Sunan aear of Jiangsu Province in China from April 2021 to July 2021 and 36 healthy controls recruited from the community during the same period were selected. Based on childhood trauma questionnaire scores, parents who had lost their only child were divided into those with childhood trauma (group A, n=55) and those without childhood trauma (group B, n=57); similarly, the healthy controls were divided into a group with childhood trauma (group C, n=12) and a group without childhood trauma (group D, n=24). All participants were evaluated by clinical scales such as Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Mini-Mental State Examination (MMSE). MRI 3D-T1 structural images and resting-state functional magnetic resonance imaging data were collected; gray matter volume (GMV) and degree centrality (DC) were calculated by standardized image preprocessing procedure, and ratio of DC to GMV within each voxel was computed to obtain the structure-function coupling map. A two-factor analysis of variance was used to analyze the independent effect and interactive effect of loss of the only child and childhood trauma on GMV, DC, and DC/GMV coupling value. Spearman rank correlation analysis was used to evaluate the associations of above indicators in brain regions with significant difference in independent effect and interactive effect with clinical scale scores. Results:(1) Compared with the participants without childhood trauma (group B+group D), the participants with childhood trauma (group A+group C) showed significantly reduced GMV in the left middle temporal gyrus and right dorsolateral superior frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, Gaussian random field [GRF] corrected). A significant interactive effect of loss of the only child and childhood trauma on GMV in the right precuneus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (2) Compared with the healthy controls, parents who had lost their only child exhibited significantly increased DC in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC in the right thalamus (voxel-level P<0.01, cluster-level P< 0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (3) Compared with the healthy controls, parents who had lost their only child showed significantly decreased DC/GMV coupling value in the left middle frontal gyrus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). Compared with participants without childhood trauma, participants with childhood trauma showed significantly increased DC/GMV coupling value in the right thalamus (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). A significant interactive effect of loss of the only child and childhood trauma on DC/GMV coupling value in the left dorsolateral superior frontal gyrus was observed (voxel-level P<0.01, cluster-level P<0.05, GRF corrected). (4) Correlation analysis revealed that GMV in the right precuneus with significant interactive effect of loss of the only child and childhood trauma was positively correlated with MMSE score ( r s=0.317, P=0.010, Bonferroni corrected). GMV in the left middle temporal gyrus with significant independent effect of childhood trauma was positively correlated with both HAMD score and HAMA score ( r s=0.362, P=0.006; r s= 0.349, P=0.008, Bonferroni corrected). Conclusion:Loss of the only child and childhood trauma can interact to jointly affect the brain structure, function, and structure-function coupling; and some of these brain structure alterations are closely associated with clinical symptoms.

Objective:To evaluate the predictive value of simplified geriatric assessment (sGA) in elderly Chinese patients diagnosed with diffuse large B-cell lymphoma (DLBCL) .Methods:It retrospectively analyzed the relationships of sGA with the clinical characteristics, outcome, and prognosis of 219 patients aged ≥60 years who were newly diagnosed with DLBCL at six hospitals in Jiangsu province between January 2018 and December 2022.Results:The median age of 219 patients was 68 years (60-87 years). According to the sGA system criteria, 101 (46.1%), 103 (47.0%), and 15 (6.8%) elderly patients with DLBCL were categorized as fit, unfit, and frail, respectively. The most common adverse reactions after chemotherapy were hematologic, and the incidence of grade >2 hematologic adverse reactions was similar among the three groups (47.5% vs 41.7% vs 46.7%, respectively; χ2=0.712, P=0.700). Compared with the fit and unfit groups, the frail group showed tendencies toward for higher proportions of grade >2 gastrointestinal, pulmonary, and infectious adverse reactions ( P>0.05 for all). The fit, unfit, and frail groups had respective remission rates of 74.3%, 46.6%, and 20.0% ( χ2=25.249, P<0.001) ; disease progression rates of 5.9%, 11.7%, and 26.7% ( χ2=6.763, P<0.05) ; 2-year overall survival rates of 92.1% (95% CI 86.6% to 97.9%), 77.6% (95% CI 69.5% to 86.6%), and 70.1% (95% CI 49.4% to 99.6%) ( P<0.05) ; and 2-year progression-free survival rates of 76.8% (95% CI 67.0% to 84.8%), 69.7% (95% CI 61.8% to 82.0%), and 65.7% (95% CI 53.3% to 100%) ( P=0.399) . Conclusion:sGA can effectively predict treatment adverse effects and efficacy, disease progression, and long-term survival in elderly DLBCL.