ObjectiveTo investigate the influence of entecavir （ETV） versus tenofovir alafenamide fumarate （TAF） on renal function in previously untreated patients with chronic hepatitis B （CHB）. MethodsA retrospective analysis was performed for the clinical data of 167 previously untreated CHB patients who received ETV or TAF treatment for at least 48 weeks at the outpatient service of Department of Infectious Diseases in The First Affiliated Hospital of Nanchang University from September 2019 to November 2023， and according to the antiviral drug used， they were divided into ETV group with 117 patients and TAF group with 50 patients. In order to balance baseline clinical data， propensity score matching （PSM） was used for matching and analysis at a ratio of 2∶1， and the two groups were compared in terms of estimated glomerular filtration rate （eGFR） and the incidence rate of abnormal renal function at week 48. According to eGFR at week 48， the patients were divided into normal renal function group and abnormal renal function group. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. The multivariate Logistic regression analysis was used to investigate the influencing factors for abnormal renal function， and the receiver operating characteristic （ROC） curve was used to assess the performance of each indicator in predicting abnormal renal function. The Kaplan-Meier method was used to analyze the cumulative incidence rate of abnormal renal function， and the log-rank test was used for comparison. The analysis of variance with repeated measures was used to compare the dynamic changes of eGFR during antiviral therapy in CHB patients. ResultsAfter PSM matching， there were 100 patients in the ETV group and 50 patients in the TAF group. There were no significant differences in baseline clinical data between the ETV group and the TAF group （all P>0.05）， with an eGFR level of 112.29±9.92 mL/min/1.73 m² in the ETV group and 114.72±12.15 mL/min/1.73 m² in the TAF group. There was a reduction in eGFR from baseline to week 48 in both groups， and compared with the TAF group at week 48， the ETV group had a significantly lower eGFR （106.42±14.12 mL/min/1.73 m² vs 112.25±13.44 mL/min/1.73 m²， t=-2.422， P=0.017） and a significantly higher incidence rate of abnormal renal function （17.00% vs 4.00%， χ²=5.092， P=0.024）. After the patients were divided into normal renal function group with 131 patients and abnormal renal function group with 19 patients， the univariate analysis showed that there were significant differences between the two groups in age （Z=-2.039， P=0.041）， treatment drug （ETV/TAF） （χ²=5.092， P=0.024）， and baseline eGFR level （t=4.023， P<0.001）， and the multivariate Logistic regression analysis showed that baseline eGFR （odds ratio ［OR］=0.896， 95% confidence interval ［CI］： 0.841 — 0.955， P<0.001） and treatment drug （OR=5.589， 95%CI： 1.136 — 27.492， P=0.034） were independent influencing factors for abnormal renal function. Baseline eGFR had an area under the ROC curve of 0.781 in predicting abnormal renal function in CHB patients， with a cut-off value of 105.24 mL/min/1.73 m²， a sensitivity of 73.68%， and a specificity of 82.44%. The Kaplan-Meier curve analysis showed that the patients with baseline eGFR≤105.24 mL/min/1.73 m² had a significantly higher cumulative incidence rate of abnormal renal function than those with baseline eGFR>105.24 mL/min/1.73 m² （χ²=22.330， P<0.001）， and the ETV group had a significantly higher cumulative incidence rate of abnormal renal function than the TAF group （χ²=4.961， P=0.026）. With the initiation of antiviral therapy， both the ETV group and the TAF group had a significant reduction in eGFR （F=5.259， P<0.001）， but the ETV group only had a significant lower level of eGFR than the TAF group at week 48 （t=-2.422， P=0.017）； both the baseline eGFR≤105.24 mL/min/1.73 m² group and the baseline eGFR>105.24 mL/min/1.73 m² group had a significant reduction in eGFR （F=5.712， P<0.001）， and there was a significant difference in eGFR between the two groups at baseline and weeks 12， 24， 36， and 48 （t=-13.927， -9.780， -8.835， -9.489， and -8.953， all P<0.001）. ConclusionFor CHB patients initially treated with ETV or TAF， ETV antiviral therapy has a higher risk of renal injury than TAF therapy at week 48.

BACKGROUND: Several randomized controlled studies have suggested that the prophylactic use of proton pump inhibitors (PPIs) in intensive care unit (ICU) patients could not reduce the incidence of gastrointestinal bleeding (GIB) and may increase adverse events such as intestinal infection and pneumonia. Gut microbiota may play a critical role in the process. PPIs have been widely prescribed for GIB prophylaxis in patients with acute coronary syndrome (ACS). This study aimed to determine the short-term effects of PPI and histamine-2 receptor antagonist (H2RA) treatment on gut microbiota of ACS patients. METHODS: The study was designed as a single-blind, multicenter, three-parallel-arm, randomized controlled trial conducted at three centers in Beijing, China. We enrolled ACS patients at low-to-medium risk of GIB and randomized (2:2:1) them to either PPI ( n = 40), H2RA ( n = 31), or control group ( n = 21). The primary outcomes were the alterations in gut microbiota after 7 days of acid suppressant therapy. Stool samples were collected at baseline and 7 days and analyzed by 16S ribosomal RNA (rRNA) gene sequencing. RESULTS: There were no significant changes in the diversity of gut microbiota after the short-term use of acid suppressants, but the abundance of Fusobacterium significantly increased and that of Bifidobacterium significantly decreased, especially in PPI users. In addition, the abundance of some pathogenic bacteria, including Enterococcus and Desulfovibrio, was significantly elevated in the PPI users. The fecal microbiota of the PPI users included more arachidonic acid metabolism than that of control group. CONCLUSIONS: PPIs may increase the risk of infection by adversely altering gut microbiota and elevating arachidonic acid metabolism, which may produce multiple proinflammatory mediators. For ACS patients at low-to-medium risk of GIB, sufficient caution should be paid when acid-suppressant drugs are prescribed, especially PPIs. REGISTRATION www.chictr.org.cn (ChiCTR2000029552).
Humans ; Proton Pump Inhibitors/therapeutic use* ; Acute Coronary Syndrome/microbiology* ; Female ; Gastrointestinal Microbiome/drug effects* ; Male ; Middle Aged ; Histamine H2 Antagonists/therapeutic use* ; Aged ; Single-Blind Method

OBJECTIVE: To investigate of effectiveness of free fascia lata flap assisted by indocyanine green angiography (ICGA) in treatment of Myerson type Ⅱ and Ⅲ chronic Achilles tendon ruptures. METHODS: A clinical data of 14 patients with Myerson type Ⅱ and Ⅲ chronic Achilles tendon ruptures between March 2020 and June 2024 was retrospectively analyzed. All Achilles tendon defects were repaired with the free fascia lata assisted by ICGA during operation. There were 12 males and 2 females with an average age of 45.4 years (range, 26-71 years). The causes of Achilles tendon rupture included sports injury in 10 cases, Achilles tendon-related tendinopathy in 3 cases, and glass laceration injury in 1 case. The time from Achilles tendon rupture to operation was 4-40 weeks (median, 4.5 weeks). Preoperative MRI examination showed that the defect length of the Achilles tendon was 2-5 cm (mean, 3.2 cm). The operation time and intraoperative blood loss were recorded. The color Doppler ultrasound (CDU) and MRI were taken to observe the foot blood vessels and the tendon healing. The visual analogue scale (VAS) score, American Orthopaedic Foot and Ankle Society (AOFAS) score, Achilles Tendon rupture score (ATRS), and range of motion of the ankle joint were used to estimate the pain and function of ankle joint. RESULTS: All operations of the 14 patients were successfully completed. The operation time ranged from 3.00 to 4.50 hours (mean, 3.60 hours). The intraoperative blood loss ranged from 10 to 50 mL (mean, 36.4 mL). After operation, 1 patient had exudation at the recipient site, which healed after dressing change; the other incisions healed by first intention. All incisions at the donor sites healed by first intention. All patients were followed up 6-36 months (mean, 11.4 months). The CDU of the foot at 1 month after operation showed that the blood flow signal of the perforating vessels of the fascia lata flap was clear. The ankle MRI at 2 months after operation showed the good continuity of the Achilles tendon. No complication such as the Achilles tendon re-rupture, ankle stiffness, or scar contracture occurred during follow-up. Compared with preoperative score, the AOFAS score, ATRS score, and plantar flexion range of motion significantly increased at 1, 3, and 6 months after operation ( P<0.05), while the VAS score and dorsiflexion range of motion significantly decreased ( P<0.05). The AOFAS score, ATRS score, and VAS score at 3 and 6 months further improved when compared with those at 1 month ( P<0.05); however, there was no significant difference in the range of motion of the ankle joint ( P>0.05). There was no significant difference in above indicators between 3 and 6 months after operation ( P>0.05). CONCLUSION The treatment of Myerson type Ⅱ and Ⅲ chronic Achilles tendon ruptures with free fascia lata flaps under the guidance of ICGA has the advantages of precise design, fast healing, and a wide range of adaptability.
Humans ; Achilles Tendon/diagnostic imaging* ; Male ; Female ; Adult ; Middle Aged ; Retrospective Studies ; Indocyanine Green ; Rupture/surgery* ; Aged ; Fascia Lata/transplantation* ; Angiography/methods* ; Free Tissue Flaps/blood supply* ; Plastic Surgery Procedures/methods* ; Tendon Injuries/diagnostic imaging* ; Treatment Outcome ; Chronic Disease

OBJECITVE: To investigate the effectiveness of three-dimensional (3D) printing-assisted vascularized fibular graft for repairing metatarsal defects. METHODS: Between November 2021 and February 2024, 11 patients with varying degrees of metatarsal defects caused by trauma were treated. There were 10 males and 1 female, aged 22-67 years, with a mean age of 51.2 years. The defect locations were as follows: the first metatarsal in 4 cases, the fifth metatarsal in 2 cases, the first and the second metatarsals in 1 case, the first to third metatarsals in 1 case, the third and the fourth metatarsals in 1 case, the third to fifth metatarsals in 1 case, and the first to fifth metatarsals in 1 case. The preoperative American Orthopaedic Foot & Ankle Society (AOFAS) score was 67.0 (48.5, 72.5). Based on 3D-printed bilateral feet models and mirrored healthy-side foot arch angles for preoperative planning and design, the vascularized fibular graft was performed to repair the metatarsal defects. At last follow-up, the medial and lateral longitudinal arches of bilateral feet were measured on weight-bearing X-ray films, and functional assessment was conducted using the AOFAS score. RESULTS: All operations were successfully completed, with an operation time ranging from 180 to 465 minutes (mean, 246.8 minutes). All incisions healed by first intention, with no occurrence of osteomyelitis. All patients were followed up 6-22 months (mean, 10 months). X-ray film reviews showed bone graft healing in all cases, with a healing time of 3-6 months (mean, 5 months). All patients underwent internal fixator removal at 6-12 months after operation. At last follow-up, no significant difference was observed in the medial and lateral longitudinal arches between the healthy and affected feet ( P>0.05). The AOFAS score of the affected foot was 78.0 (73.5, 84.0), showing a significant improvement compared to the preoperative score ( P<0.05). The effectiveness was rated as excellent in 1 case, good in 7 cases, fair in 2 cases, and poor in 1 case. Linear scarring remained at the donor site, with no functional impairment in adjacent joint movement. CONCLUSION 3D printing-assisted vascularized fibular graft for repairing metatarsal defects can effectively restore the physiological angle of the foot arch, facilitate the recovery of weight-bearing alignment, promote good bone healing, and yield satisfactory clinical outcomes.
Humans ; Printing, Three-Dimensional ; Middle Aged ; Male ; Fibula/blood supply* ; Female ; Metatarsal Bones/injuries* ; Adult ; Bone Transplantation/methods* ; Aged ; Plastic Surgery Procedures/methods* ; Young Adult ; Treatment Outcome

G protein-coupled receptor kinase 2 (GRK2) participates in the phosphorylation and desensitization of G protein-coupled receptor (GPCR), impacting various biological processes such as inflammation and cell proliferation. Dysregulated expression and activity of GRK2 have been reported in multiple cells in rheumatoid arthritis (RA). However, whether and how GRK2 regulates synovial hyperplasia and fibroblast-like synoviocytes (FLSs) proliferation is poorly understood. In this study, we investigated the regulation of GRK2 and its biological function in RA. We found that GRK2 transmembrane activity was increased in FLSs of RA patients and collagen-induced arthritis (CIA) rats. Additionally, we noted a positive correlation between high GRK2 expression on the cell membrane and serological markers associated with RA and CIA. Immunoprecipitation-mass spectrometry and pull-down analyses revealed tumor necrosis factor receptor-associated factor 2 (TRAF2) as a novel substrate of GRK2. Furthermore, surface plasmon resonance (SPR) and molecular docking assays determined that the C-terminus of GRK2 binds to the C-terminus of TRAF2 at the Gln340 residue. GRK2 knockdown and the GRK2 inhibitor CP-25 attenuated synovial hyperplasia and FLS proliferation in CIA both in vitro and in vivo by decreasing GRK2 membrane expression and activity. Mechanistically, increased GRK2 transmembrane activity contributed to the recruitment of TRAF2 on the cell membrane, promoting GRK2-TRAF2 interactions that facilitate the recruitment of the E3 ubiquitin ligase TRIM47 to TRAF2. This enhanced TRAF2 Lys63 polyubiquitylation and induced nuclear factor (NF)-κB activation, leading to synovial hyperplasia and abnormal proliferation of FLSs. Our study provides a mechanistic and preclinical rationale for further evaluation of GRK2 as a therapeutic target for RA.

Rapid and ultrasensitive detection of pathogen-associated biomarkers is vital for the early diagnosis and therapy of bacterial infections. Herein, we developed a close-packed and ordered Au@AgPt array coupled with a cascade triggering strategy for surface-enhanced Raman scattering (SERS) and colorimetric identification of the Staphylococcus aureus biomarker micrococcal nuclease (MNase) in serum samples. The trimetallic Au@AgPt nanozymes can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) molecules to SERS-enhanced oxidized TMB (oxTMB), accompanied by the color change from colorless to blue. In the presence of S. aureus, the secreted MNase preferentially cut the nucleobase AT-rich regions of DNA sequences on magnetic beads (MBs) to release alkaline phosphatase (ALP), which subsequently mediated the oxTMB reduction for inducing the colorimetric/SERS signal fade away. Using this "on-to-off" triggering strategy, the target S. aureus can be recorded in a wide linear range with a limit of detection of 38 CFU/mL in the colorimetric mode and 6 CFU/mL in the SERS mode. Meanwhile, the MNase-mediated strategy characterized by high specificity and sensitivity successfully discriminated between patients with sepsis (n = 7) and healthy participants (n = 3), as well as monitored the prognostic progression of the disease (n = 2). Overall, benefiting from highly active and dense "hot spot" substrate, MNase-mediated cascade response strategy, and colorimetric/SERS dual-signal output, this methodology will offer a promising avenue for the early diagnosis of S. aureus infection.

Objective: To investigate whether TYRO protein tyrosine kinase-binding protein (TYROBP) affects the progression of diabetic kidney disease (DKD) through the extracellular signal-regulated kinase ( ERK) pathway. Methods: Key genes in DKD were identified through bioinformatics analysis . Immunohistochemical staining and quantitative real-time PCR (qPCR) were used to validate the expression levels of TYROBP in a DKD mouse model and high glucose-stimulated NRK-52E cells . NRK-52E cell models with stable TYROBP overexpression/knockdown and their corresponding empty vector (ev) /scrambled sequence (ss) controls were established via lentiviral trans- fection . Cells were treated with 5 . 5 mmol/L or 30. 0 mmol/L glucose for 72 hours to mimic normal glucose (NG) and high glucose ( HG) conditions , respectively. High glucose medium containing 3 . 5 μmol/L FR180204 was used for ERK inhibitor intervention . The experiment included seven groups : ev + NG , ev + HG , oe-TYROBP + HG , ss + NG , ss + HG , sh-TYROBP + HG , and sh-TYROBP + HG + ERK inhibitor. Western blot was used to de- tect the expression levels of phosphorylated ERK/total ERK (p-ERK/ERK) , apoptosis-related proteins B-cell lym- phoma-2 (Bcl-2) and Bcl-2-associated X protein ( Bax) , and epithelial-mesenchymal transition ( EMT)-related proteins E-cadherin and α-smooth muscle actin ( α-SMA) . Tetramethylrhodamine ethyl ester (TMRE) staining and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) flow cytometry were performed to as- sess mitochondrial membrane potential and apoptosis levels . Results: Bioinformatics analysis identified TYROBP as a key gene in DKD . In vivo and in vitro validation showed increased TYROBP mRNA levels in DKD models . The results from the HG model indicated that , compared to the ev + NG/ss + NG group , the ev + HG/ss + HG group demonstrated increased p-ERK/ERK expression , reduced mitochondrial membrane potential , elevated apoptosis , and enhanced EMT. In TYROBP-perturbed NRK-52E cells , compared to the ev + HG group , the oe-TYROBP + HG group showed decreased p-ERK/ERK expression (P < 0. 01) , increased mitochondrial membrane potential (P < 0. 05) , reduced apoptosis (P < 0. 001) , and attenuated EMT; whereas compared to the ss + HG group , the sh- TYROBP + HG group exhibited increased p-ERK/ERK expression ( P < 0. 001) , decreased mitochondrial mem- brane potential (P < 0. 01) , elevated apoptosis (P < 0. 001) , and enhanced EMT. Furthermore , compared to the sh-TYROBP + HG group , the sh-TYROBP + HG + ERK inhibitor group displayed reduced p-ERK/ERK expression (P < 0. 01) , increased mitochondrial membrane potential ( P < 0. 001) , decreased apoptosis ( P < 0. 001) , and suppressed EMT. Compared with the scrambled sequence control + high glucose group , the TYROBP knockdown + high glucose group showed elevated p-ERK/ERK expression ( P < 0. 001) , reduced mitochondrial membrane potential (P < 0. 01) , increased apoptosis level (P < 0. 001) , and enhanced EMT. Compared with the TYROBP knockdown + high glucose group , the TYROBP knockdown + high glucose + ERK inhibitor group demonstrated decreased p-ERK/ERK expression (P < 0. 01) , restored mitochondrial membrane potential (P < 0. 001) , reduced apoptosis level (P < 0. 001) , and suppressed EMT. Conclusion TYROBP may regulate the ERK signaling path- way to modulate apoptosis- and EMT-related proteins , thereby influencing mitochondrial membrane potential , apop- tosis , and EMT in renal tubular epithelial cells and contributing to DKD progression .

ObjectiveTo use the maternal morbidity WOICE Tool（Chinese version）to investigate the maternal morbidity in Shanghai， and to examine the current situation and associated factors of adverse symptoms and impaired functioning in the third trimester and postpartum period. MethodsPregnant women who made their initial visit and established a medical record at a tertiary obstetrics and gynecology hospital in Shanghai from March to August 2021 were recruited and a baseline survey was completed. The prevalence of maternal morbidity was surveyed in the third trimester and first 6 weeks postpartum. ResultsSelf-reported adverse physical symptoms were observed in 89.8% of women in the third trimester and 86.1% in first 6 weeks postpartum. The prevalence rates of anxiety and depression were 4.1% and 6.2% in the third trimester， and 6.2% and 7.5% in first 6 weeks postpartum， respectively. The proportions of women reporting impaired functioning were 80.3% in the third trimester and 64.1% in first 6 weeks postpartum， respectively. Physical symptoms were associated with parity， education， the newborn’s health status， and risk of experiencing violence. Psychological symptoms were associated with age， household responsibilities， employment status， the newborn’s health status， pre-pregnancy body mass index （BMI）， and risk of experiencing violence. Functionality was associated with the type of registered residence， education level， household responsibilities， and risk of experiencing violence. ConclusionThe physical health status of pregnant and postpartum women in Shanghai is better than that in the middle-income regions abroad， with anxiety and depression at average levels compared to national statistics in China. Physical， psychological， and functional status are affected by multiple factors including personal， health， family， and work conditions. Preventive measures should be taken from various perspectives to mitigate adverse symptoms and impaired functioning， and to improve the positive experience of pregnancy and childbirth.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective To find the correlation between phosphatidylinositol kinase-3 catalytic subunit A gene(PIK3CA)mutation and pathological features as well as clinical prognosis of breast cancer.Methods The patho-logical data of 181 patients diagnosed with invasive breast cancer from January 2018 to January 2020 were collected.The estrogen receptor(ER),progestogen receptor(PR),human epidermal growth factor receptor-2(HER2),Ki67 were examined by immuno-histochemistry(IHC).Mutation of exon 9 and exon 20 of PIK3CA were examined by quantitative real-time PCR(qPCR).Results Among 181 cases of invasive breast cancer,70 cases had PIK3CA mutation with 31 cases(44.28%)showed exon 9 mutations and 39 cases(55.71%)showed exon 20 mutations.The difference between PIK3CA mutation and their distribution in molecular typing of breast cancer was statistically significant(P＜0.05).The expression of PIK3CA mutation in breast cancer with different Ki67 expression was sig-nificantly different(P＜0.05).There were 34 cases(48.57%)showed PIK3CA mutations in the HR+/HER2 group and 36 cases(51.43%)of non HR+/HER2 group mutations.There was a statistically significant difference in the distribution of PIK3CA mutations between 2 groups(P＜0.05).The death rate of PIK3CA mutation cases was higher than that of PIK3CA wild type cases(P＜0.05).Conclusions PIK3CA mutation is associated with molecular typ-ing,Ki67 increment index and prognosis of breast cancer.Detection of PIK3CA mutation provides potential support to the development of precise treatment of breast cancer patients.