Objective:To investigate the association between serum uric acid trajectories and the risk of renal function decline and diabetic kidney disease(DKD) incidence in elderly patients with type 2 diabetes mellitus.Methods:This retrospective cohort study included 5 037 elderly patients with type 2 diabetes mellitus aged 60 years and above who underwent at least three health examinations between 2019 and 2023, with 2019 as the baseline. Latent growth mixture modeling(LGMM) was employed to identify distinct serum uric acid trajectories. Renal function changes and DKD incidence were followed from 2020 to 2023. Binary logistic regression models were used to assess the association between serum uric acid trajectories and the risks of renal function decline and DKD.Results:Two distinct serum uric acid trajectory groups were identified based on model selection criteria: A stable group( n=4 485, 89.04%) and an inverted U-shaped group( n=552, 10.96%). After adjusting for potential confounders, compared with the stable trajectory group, the inverted U-shaped group showed a significantly increased risk of estimated glomerular filtration rate(eGFR) <60 mL·min -1·(1.73 m 2) -1, ≥25% decline in eGFR, doubling of serum creatinine, and DKD events, with OR(95% CI) of 1.99(1.28-3.09), 2.27(1.65-3.13), 1.52(1.09-3.02), and 1.52(1.27-1.82), respectively(all P<0.05). In addition, multivariate analysis indicated that elevated baseline serum uric acid levels were also associated with an increased risk of adverse renal outcomes and DKD incidence; However, the magnitude of the associations was lower than that observed for serum uric acid trajectory groups. Conclusions:An inverted U-shaped serum uric acid trajectory is significantly associated with an increased risk of renal function progression and DKD in elderly patients with type 2 diabetes mellitus. These findings highlight the importance of long-term dynamic monitoring of serum uric acid levels to facilitate early identification and intervention for high-risk individuals.

Tenosynovial giant cell tumor (TGCT) is a rare mesenchymal tumor that clinically presents as nodular-type or diffuse-type (D-TGCT). D-TGCT is more aggressive, has a higher surgical recurrence rate, and can potentially lead to severe joint destruction. The traditional treatment is primarily through surgical intervention. Recent advancements in understanding the molecular mechanisms of the disease and the development of new drugs have significantly changed TGCT treatment strategies. Drug therapy and active surveillance have become important treatment options for unresectable or high-recurrence-risk TGCT. Imaging examinations and patient-reported outcome tools play a crucial role in evaluating efficacy and guiding treatment decisions. Comprehensive management by a multidisciplinary team and utilizing individualized treatment plans can significantly improve the quality of life and treatment outcomes of patients. Future research should explore the molecular mechanisms of TGCT, enhance multidisciplinary collaboration, and emphasize long-term management to improve treatment efficacy and patient prognosis.

Objective To investigate the clinical efficacy of Guhong Injection for the treatment of patients with coronary microvascular dysfunction(CMD)of qi stagnation and blood stasis syndrome.Methods Sixty cases of patients with CMD of qi stagnation and blood stasis syndrome who were admitted to Guangdong Provincial Hospital of Chinese Medicine from June 2021 to August 2022 were randomly divided into the control group and the trial group according to the random number table method,with 30 cases in each group.The control group was treated with conventional western medicine,and the trial group was treated with Guhong Injection on the basis of treatment for the control group.The course of treatment for the two groups covered 10 days.The changes in traditional Chinese medicine(TCM)syndrome scores,and levels of lipid indicators,serum inflammatory factors and endothelial factors in the two groups were observed before and after treatment.After treatment,the clinical efficacy of the two groups was evaluated.Results(1)During the trial,three cases in the control group and two cases in the trial group fell off and a total of 55 cases were finally included in the statistical analysis of efficacy,including 27 cases in the control group and 28 cases in the trial group.(2)After 10 days of treatment,the total effective rate of the trial group was 89.29%(25/28),and that of the control group was 40.74%(11/27),and the intergroup comparison(tested by chi-square test)showed that the therapeutic efficacy of the trial group was significantly superior to that of the control group(P<0.01).(3)After treatment,the TCM syndrome scores of patients in both groups were decreased compared with those before treatment(P<0.05),and the decrease in the trial group was significantly superior to that in the control group(P<0.01).(4)After treatment,the levels of lipid indicators triglyceride(TG),total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)in the two groups of patients were decreased compared with those before treatment(P<0.05),and the level of high-density lipoprotein cholesterol(HDL-C)was increased compared with that before treatment(P<0.05).The intergroup comparison showed that the decrease of TG,TC,and LDL-C levels as well as the increase of HDL-C level in the trial group was significantly superior to that in the control group(P<0.05 or P<0.01).(5)After treatment,the serum levels of inflammatory factors high-sensitivity C-reactive protein(hs-CRP),interleukin 6(IL-6)and tumor necrosis factor α(TNF-α)in the two groups of patients were decreased compared with those before treatment(P<0.05),and the decrease in the trial group was significantly superior to that in the control group(P<0.01).(6)After treatment,the serum level of endothelial factor nitric oxide(NO)in the two groups of patients was increased(P<0.05)and the serum endothelin 1(ET-1)level was decreased compared with that before treatment(P<0.05),and the increase of serum NO level,as well as the decrease of serum ET-1 level in the trial group was significantly superior to that in the control group(P<0.05 or P<0.01).Conclusion Based on the conventional treatment in western medicine,the application of Guhong Injection in the treatment of patients with CMD of qi stagnation and blood stasis syndrome exerts remarkable efficacy,which can effectively alleviate the symptoms,regulate the levels of blood lipids,reduce the inflammatory response,and improve the endothelial function.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective To use AI-assisted motor dysfunction assessment for quantitative evaluation of motor function in Parkinson's disease(PD)and multiple system atrophy-Parkinsonian type(MSA-P)in order to achieve accurate differential diagnosis.Methods A total of 105 participants aged ≥60 years were consecutively enrolled from the First and Third Medical Centers of Chinese PLA General Hospital between January and September 2024.Based on diagnostic criteria,they were divided into a PD group(48 cases),a MSA-P group(31 cases),and a control group(26 cases).The general information was collected,and the motor function was evaluated with Move-ment Dysfunction Assessment Software in order to assess the diagnostic value of the AI-assisted assessment in differentiating between PD and MSA-P.Results Significantly differences were observed among the three groups in terms of facial expression indicators,bilateral finger tapping frequency,bilateral hand movement frequency,right hand movement amplitude change rate,bilat-eral palm flipping frequency,bilateral toe tapping frequency,freezing load of bilateral toe tapping,bilateral leg flexibility frequency,right leg flexibility amplitude change rate,freezing load of bilat-eral leg flexibility,upright extension angular velocity,turnaround time,forward step frequency,backward step frequency,forward average stride length,backward average stride length,forward average walking speed,backward average walking speed,forward average step width,backward average step width,bilateral postural tremor frequency,bilateral postural tremor maximum am-plitude,bilateral action tremor frequency,bilateral action tremor maximum amplitude,and com-parison of bilateral resting tremor frequency(P＜0.05,P＜0.01).The MSA-P group exhibited significantly lower blink frequency,maximum amplitude and frequency of facial tremors,upright extension angular velocity,and step frequency,while higher ratio of mouth opening duration and longer turnaround time when compared with the PD group(P＜0.05,P＜0.01).The AUC value of the combined nine motor function indicators and the five facial expression indicators in differ-entiating PD from MSA-P was 0.943(95％CI:0.895-0.991,P=0.000)and 0.925(95％CI:0.870-0.981,P=0.000),respectively,both better than that of individual indicators.Conclusion Combi-nation assessment of facial expression,posture,gait with AI assistance can contribute to the dif-ferential diagnosis of PD and MSA-P.

Objective To explore the relationship between plantar fascia stiffness and windlass mechanism and their impact on the arch,and provide a biomechanical mechanism explanation for plantar fascia and arch-related diseases.Methods A foot-plate model with 30° flexion angle at the metatarsophalangeal joint was constructed.The musculoskeletal model combined with the three-dimensional finite element analysis method was used,and the dynamic data of the foot during walking at the speed of 5 km/h was obtained using dual fluoroscopic imaging system(DFIS).The finite element model was verified,and the influence of plantar fascia stiffness on the capstan mechanism and arch-related mechanical parameters was explored.Results The finite element simulation analysis results were highly consistent with the foot data obtained by DFIS,confirming the validity of the model.With the increase of plantar fascia stiffness,the windlass effect and the stiffness of the longitudinal arch of the foot both showed an increasing trend,but the flexion angle of the metatarsophalangeal joint decreased,the distal stress of the plantar fascia gradually decreased,and the proximal stress increased;when the plantar fascia stiffness was 25％-150％,the width of the transverse arch of the foot increased with the increase of plantar fascia stiffness,while the height of the transverse arch decreased with the increase of plantar fascia stiffness;when the plantar fascia stiffness was 150％-200％,the width of the transverse arch of the foot decreased,the height increased,and the stiffness also increased.Conclusions An increase in plantar fascia stiffness can enhance the windlass mechanism to some extent,but it also leads to a reduction in metatarsophalangeal joint flexion.The stiffness of the plantar fascia affects the metatarsophalangeal joint flexion,thereby impacting the windlass mechanism and the distal tensile force of the plantar fascia.Together with the ground reaction force at the distal end of the metatarsals,these factors collectively influence the stiffness of the transverse arch of the foot.

Objective:To understand nurses' experiences providing discharge preparation services for elderly patients with multiple chronic diseases and offer references for developing intervention strategies for discharge preparation services for these patients.Methods:A purposive sampling method was used to select 24 nurses from the cardiovascular departments, geriatrics wards, and other internal medicine departments of three Grade A tertiary hospitals, four Grade B hospitals, and one community health service center in Guilin City between March and April 2024. An interview outline was developed based on the social-ecological system theory, and semi-structured interviews were conducted to collect data. A directed content analysis method was used to analyze the data.Results:A total of three themes were identified: micro-level (nurses have a positive attitude but face shortcomings in age-appropriate discharge preparation services), meso-level (team collaboration mechanisms are weak), and macro-level (there is a desire to link social resources) .Conclusions:Nurses' discharge preparation services for elderly patients with multiple chronic diseases are inadequate. It is recommended to enhance nurses' discharge preparation skills through core competency-based training, improve the development of innovative healthcare platforms, and promote establishing of a multi-dimensional social care support system to improve the quality of discharge preparation services for elderly patients with multiple chronic diseases.