AIM: To evaluate the clinical efficacy of intense pulsed light(IPL)therapy in patients with primary Sjogren's syndrome-related dry eye(SS-DE).METHODS:In this prospective randomized trial, 82 cases(82 eyes)diagnosed with moderate-to-severe SS-DE at our hospital from January 2023 to December 2023 were selected. If both eyes meet the criteria, one eye will be randomly selected for inclusion, and if one eye meets the inclusion criteria, the eye will be selected for enrollment. They were randomly assigned to either an experiment group receiving dextran hydroxypropyl methylcellulose eye drops and 0.05% cyclosporine A eye drops plus IPL therapy, or a control group receiving dextran hydroxypropyl methylcellulose eye drops and 0.05% cyclosporine A eye drops. Ocular surface disease index(OSDI)score, tear meniscus height(TMH), noninvasive tear breakup time(NITBUT), meibomian gland loss score, Schirmer I test(SⅠt), corneal fluorescein staining(CFS)score, conjunctival lissamine green staining(CLGS)score, lipid layer thickness(LLT), blink frequency, corneal Langerhans cell density(CLCD)and complications of both groups were assessed at baseline and at 4, 8, and 12 wk after treatment.RESULTS:There were 6 cases lost to follow-up in the experiment group, with a missing rate of 14.6%, and 1 case was lost to follow-up in the control group, with a missing rate of 2.4%, and valid data were eventually obtained from 35 cases(35 eyes)in the experiment group and 40 cases(40 eyes)in the control group. Baseline parameters did not differ significantly between the two groups of patients(all P>0.05). At 4, 8 and 12 wk after treatment, both groups showed significant reductions in OSDI scores, CFS scores, CLGS score, blink frequency, and CLCD, while the reductions were significantly greater in the experiment group compared to the control group(all P<0.05). The experiment group also demonstrated significant increases in TMH, SⅠt, and NITBUT at 4, 8 and 12 wk after treatment, which were significantly greater than those observed in the control group(all P<0.05). No significant intergroup differences were observed in LLT, meibomian gland loss score in the experiment group at any time point(all P>0.05). Furthermore, no severe ocular or cutaneous complications were associated with IPL treatment.CONCLUSION:IPL significantly improves ocular signs and symptoms, enhances aqueous tear secretion, and reduces ocular surface inflammation in patients with SS-DE, with no significant adverse reactions observed.

Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y₁₂ receptor through its active metabolite. However, the observed discrepancies between the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel present substantial challenges in individualizing of antiplatelet therapy. To address these challenges, a robust liquid chromatography-tandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y₁₂ receptor occupancy. This method has been validated in animal models, providing a reliable link between individual PK profiles and PD effects. Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism, regulation of P2Y₁₂ receptor expression, and platelet turnover. Moreover, it directly correlates with the inhibitory effect on platelet aggregation. The levels of platelet P2Y₁₂ occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel, including dosage, drug-drug interactions (DDI), and type 2 diabetes mellitus (T2DM). As a normalized metric, platelet P2Y₁₂ occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y₁₂ signaling pathway in cases of abnormal on-treatment platelet reactivity.

To better promote the development of film-coated formulations and membrane agents, the present study was carried out to investigate the critical material attributes (CMAs) of different sources and models of HPMC in terms of film-coating performance and the correlation between each of the CMAs and the film-coating-related properties, using 2910 HPMC as the research target. Firstly, various analytical techniques were used to characterize the CMAs and film coating-related properties of HPMC. Secondly, the CMAs and film coating-related properties of HPMC were systematically evaluated by principal component analysis (PCA) and orthogonal partial least-squares discrimination analysis (OPLS-DA). The CMAs and film-coating-related properties of HPMC were systematically evaluated to elucidate the intrinsic relationship between the CMAs and film-coating-related properties of HPMC. The results showed that there were significant differences in viscosity, weight-average molecular weight, film tensile strength, elongation, elastic modulus, dissolution time, and flexibility of HPMCs from different manufacturers. The results of PCA and OPLS-DA analyses indicated that these 11 variables showed some correlations with each other. Both mathematical models showed better differentiation and classification of HPMC samples, and the OPLS-DA model had a better classification effect than the PCA model. Therefore, in this study, the physicochemical properties and the film-forming characteristic of HPMC were comprehensively evaluated, and the correlation between them was further established using PCA and OPLS-DA. The impact degree of different CMAs on the film coating performance of HPMC was clarified, which can be used as an important reference for the selection of excipient quality control programs in excipient production and formulation research and development.

Objective:To investigate the effects of Porphyromonas gingivalis derived outer membrane vesicles (Pg OMV) on osteoclast differentiation of macrophages and its underlying mechanisms. Methods:The morphology and the size distribution of Pg OMV were analyzed by transmission electron microscopy and nanoparticle tracing analysis, respectively. The osteoclast precursors were treated with 1, 3 and 10 mg/L Pg OMV (1, 3 and 10 mg/L OMV treatment group) or phosphate buffer solution (PBS)(control group). The formation of osteoclasts was analyzed by tartrate-resistant acid phosphase (TRAP) staining and F-actin staining and real-time quantitative PCR (RT-qPCR) were used to detect the expression of Fos and matrix metallopeptidase 9 (MMP9). Polymyxin B (PMB) was used to block lipopolysaccharide (LPS) and then Pg OMV was used to treat osteoclast precursor (PMB-OMV treatment group), and OMV treatment group was used as control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The effect of Pg OMV on the expression of Toll-like receptor (TLR) 2 and TLR4 in preosteoclasts was detected by Western blotting. The osteoclast precursors were pretreated with 10, 50, 100 and 200 μmol/L C29, an inhibitor of TLR2, and then treated with Pg OMV(OMV+10, 50, 100 and 200 μmol/L C29 treatment group) and OMV treatment group without C29 pretreatment was control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The osteoclast precursor cells were treated with OMV (OMV treatment group) and OMV incubated with PMB (PMB-OMV treatment group) and the expression of TLR2 in osteoclast precursor was detected by Western blotting.Results:Pg OMV showed classical vesicular structures, and the average particle size of Pg OMV were 179.2 nm. A large number of actin rings were observed in the 3 and 10 mg/L OMV treatment groups. The percentages of TRAP-positive osteoclast area in 3 mg/L OMV treatment group [(22.6±2.1)%] and 10 mg/L OMV treatment group [(32.0±2.3)%] were significantly increased compared with control group [(4.9±0.5)%] ( P<0.001). Compared with the control group (1.000±0.029), the mRNA relative expression of Fos in 3 mg/L OMV treatment group (1.491±0.114) and 10 mg/L OMV treatment group (1.726±0.254) was significantly increased ( P=0.013, P=0.001). Compared with the control group (1.007±0.148), the mRNA relative expression of MMP9 in the group of 10 mg/L OMV (2.232±0.097) was significantly increased ( P<0.001). Actin ring formation was less in PMB-OMV treatment groups than in OMV treatment groups. The proportion of TRAP-positive osteoclasts area [(14.8±3.8)%] in PMB-OMV treatment group was significantly lower than OMV treatment group [(31.5±6.7) %] ( P=0.004). The relative expression of TLR2 in OMV treatment group (1.359±0.134) was significantly higher than that in the control group (1.000±0.000) ( t=4.62, P=0.044). Compared with the OMV treatment group [(29.4±1.7)%], 50, 100 and 200 μmol/L C29 significantly decreased the formation of osteoclasts [(24.0±1.7)%, (18.5±2.1)%, (9.1±1.3) %] ( P=0.026, P<0.001, P<0.001). TLR2 protein expression in PMB-OMV group (0.780±0.046) was significantly lower than that in OMV group (1.000±0.000)( t=8.32, P=0.001). Conclusions:Pg OMV can promote osteoclast differentiation by carrying LPS, TLR2 plays an important role in Pg OMV mediated osteoclast differentiation.

Objective:To investigate HER2 mRNA expression in breast cancer with HER2 immunohistochemistry (IHC) 0 and to analyze the feasibility of distinguishing between the tumor with HER2 μltra-low expression and the one without expression of HER2 (no staining by IHC) by HER2 mRNA level preliminarily.Methods:HER2 mRNA was analyzed by reverse transcription digital PCR in 41 cases of formalin-fixed paraffin-embedded surgical tissue samples of invasive breast cancer obtained between January 2020 and March 2023 at Peking Union Medical College Hospital. The cohort included 21 HER2 IHC 1+ and 20 IHC 0 (12 ultra-low and 8 non-expression of HER2). HER2 mRNA expression level was quantitatively evaluated by the FAM (HER2)/VIC (reference gene) ratio.Results:The expression of HER2 mRNA for the cases with 1+, ultra-low, and non-expression of HER2 by IHC was 0.30 to 1.78 (average 0.90, median 0.82), 0.55 to 1.51 (average 0.93, median 0.90) and 0.22 to 0.78 (average 0.41, median 0.36), respectively. For the mean and median HER2 mRNA levels, there was no significant difference between HER2 IHC 1+ and HER2 ultra-low expression diseases ( P=0.757). A remarkable difference in HER2 gene expression was found between the tumors with 1+ and non-expression of HER2 by IHC ( P=0.002). And, HER2 ultra-low cases contained statistically higher levels of HER2 mRNA compared with non-expression of HER2 subgroup by IHC ( P=0.001). Conclusions:Based on HER2 mRNA, HER2 non-expression and HER2 weak expression (including HER2 IHC 1+ and ultra-low) belong to two different types of the tumor and the disease with HER2 IHC 1+ and HER2 ultra-low expression may be the same. It is necessary to further test the performance of HER2 mRNA detection for stratifying the HER2 weak expression subgroup and to determine the threshold.

The spectrum of biopsy-confirmed kidney disease varies with regions and periods. We describe the distribution of pathological types and epidemiological characteristics of kidney diseases in Northwest China due to regional differences in geographical environment, social economy, and dietary habits. Methods: Kidney biopsy cases from 2005 to 2020 in Xijing Hospital were retrospectively analyzed. Pathological characteristics of patients in different periods were analyzed using the t test or chi-square test. Joinpoint regression was used to analyze trends in pathological types and disease spectrum. Results: A total of 10,528 eligible patients were included. Primary glomerular disease (PGD) accounted for the majority of the cases and exhibited an obvious downward trend, whereas secondary glomerular disease (SGD) showed an obvious upward trend. Among PGD, immunoglobulin A nephropathy (IgAN) remained the most common pathological type, and the detection rate of membranous nephropathy (MN) was significantly increased. Among SGD, Henoch-Schönlein purpura nephritis (HSPN) was the most common pathological type and may present a significant characteristic of Northwest China. Diabetic nephropathy (DN) exhibited the most obvious upward trend in the whole process, whereas the fastest growth since 2012 was in hypertensive nephropathy. Conclusion: The proportion of SGD increased whereas PGD declined. IgAN remained the most common PGD, and HSPN was the most common SGD. MN and DN showed the most obvious upward trend among PGD and SGD, respectively. Changes in the spectrum of kidney disease, especially the constituent ratio of SGD, pose a great challenge to public health.

OBJECTIVES: Major depressive disorder (MDD) patients with anhedonia tend to have a poor prognosis. The underlying imaging basis for anhedonia in MDD remains largely unknown. The relationship between nodal properties and anhedonia in MDD patients need to be further investigated. Herein, this study aims to explore differences of cerebral functional node characteristics in MDD patients with severe anhedonia (MDD-SA) and MDD patients with mild anhedonia (MDD-MA) before and after the antidepressant treatment. METHODS: Ninety participants with current MDD were recruited in this study. 24-Item Hamilton Depression Scale (HAMD-24) and Snaith-Hamilton Pleasure Scale (SHAPS) were used to assess the severity of depression and anhedonia at baseline and the end of 6-months treatment. The MDD patients who scored above the 25th percentile on the SHAPS were assigned to an MDD-SA group (n=19), while those who scored below the 25th percentile were assigned to an MDD-MA group (n=18). All patients in the 2 groups received antidepressant treatment. Functional magnetic resonance imaging (fMRI) images of all the patients were collected at baseline and the end of 6-months treatment. Graph theory was applied to analyze the patients' cerebral functional nodal characteristics, which were measured by efficiency (e_i) and degree (k_i). RESULTS: Repeated measures 2-factor ANCOVA showed significant main effects on group on the e_i and k_i values of left superior frontal gyrus (LSFG) (P=0.003 and P=0.008, respectively), and on the e_i and k_i values of left medial orbital-frontal gyrus (LMOFG) (P=0.004 and P=0.008, respectively). Compared with the MDD-MA group, the significantly higher e_i and k_i values of the LSFG (P=0.015 and P=0.021, respectively), and the significantly higher e_i and k_i values of the LMOFG (P=0.015 and P=0.037, respectively) were observed in the MDD-SA group at baseline. Meanwhile, higher SHAPS scores could result in higher e_i and k_i values of LSFG (P=0.019 and P=0.026, respectively), and higher e_i value of LMOFG (P=0.040) at baseline; higher SHAPS scores could result in higher e_i values of LSFG (P=0.049) at the end of 6-months treatment. The multiple linear regression analysis revealed that sex were negatively correlated with the e_i and k_i values of LSFG (r= -0.014, P=0.004; r=-1.153, P=0.001, respectively). The onset age of MDD was negatively correlated with the k_i value of LSFG (r=-0.420, P=0.034) at the end of 6-months treatment. We also found that SHAPS scores at baseline were positively correlated with the HAMD-24 scores (r=0.387, P=0.022) at the end of 6-months treatment. CONCLUSIONS There are obvious differences in nodal properties between the MDD-SA and the MDD-MA patients, such as the high e_i of LSFG in the MDD-SA patients, which may be associated with the severity of anhedonia. These nodal properties could be potential biomarkers for the prognosis of MDD. The increased e_i and k_i values in the LSFG of MDD-SA patients may underlie a compensatory mechanism or protective mechanism. The mechanism may be an important component of the pathological mechanism of MDD-SA. The poor prognosis in the MDD-SA patients suggests that anhedonia may predict a worse prognosis in MDD patients. Sex and onset age of MDD may affect the nodal properties of LSFG at baseline and the end of 6-months treatment.
Anhedonia ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Prefrontal Cortex

As an important tumor driver gene, epidermal growth factor receptor (EGFR) gene plays an important role in the development and progression of non-small cell lung cancer (NSCLC). As the latest generation of EGFR-tyrosine kinase inhibitor (TKI) drugs, osimertinib has brought significant therapeutic efficacies and encouraging results both in patients with sensitive EGFR mutations and patients with rare EGFR mutations. Compared with previous EGFR-TKI drugs, osimertinib has strong blood-brain barrier penetration, which can effectively prevent the occurrence of lung cancer brain metastasis. After the resistance of first and second generation of targeted drugs, osimertinib is still effective in the follow-up treatment process. This article reviews the characteristics of EGFR mutation, the action mechanism of osimertinib, and the latest progress of osimertinib in treatment of EGFR mutations in NSCLC.

Objective:To investigate the influence of indoxyl sulfate(IS), a typical protein-bound uremic toxin, on left atrial (LA) functional strains using three-dimensional speckle tracking echocardiography (3DSTE).Methods:From May 2019 to January 2020, 128 individuals were consecutively enrolled, including 37 healthy controls and 91 patients, who received maintenance hemodialysis (MHD) in the blood purification center of Zhongshan Hospital affiliated to Fudan University. Conventional echocardiographic parameters and 3DSTE datas of LA were obtained on interdialytic days.LA reservoir, conduit and contraction strains (LASr, LAScd and LASct) were calculated and compared. IS concentration in plasma was assessed by high-performance liquid chromatography tandem mass spectrometry in the MHD cohort.According to the IS concentration, the MHD group was divided into high and low IS (HI and LI) groups. The LA data were also compared between the two groups and linear regression analysis was used to identify independent impact factors of LA strains.Results:Compared to the control group, MHD group had markedly enlarged LA volumes( P<0.05). With regard to the LA phasic strains, both of LASr and LAScd were decreased( P<0.05), while LASct remained unchanged( P>0.05). Compared to the LI group, LASr, LAScd and LASct of the HI group were significantly decreased(all P<0.05). Correlation analysis showed IS concentration correlated well with LASr( rs=-0.674, P<0.001), LAScd( rs=0.454, P<0.001) and LASct( rs=0.376, P<0.001). After adjustment of age, systolic blood pressure, left ventricular mass index(LVMI), and pulmonary systolic pressure, IS concentration remained independently associated with LASr (β=-0.206, 95% CI=-0.353--0.059, P=0.007). Conclusions:In MHD patients, LA is enlarged, and its reservoir function and conduit function are impaired.LA strains derived from 3DSTE are independently related to the IS concentration in plasma, which can be used for the monitoring and evaluation of IS induced cardiac injury.