Fengxiao Zhang

Interstitial lung disease (ILD) is a severe extraglandular complication of primary Sjögren's syndrome (pSS) that significantly impacts prognosis, yet non-invasive diagnostic tools remain limited in rheumatology practice. This study aimed to evaluate the association between serum growth differentiation factor 15 (GDF-15) and prevalent pSS-associated ILD (pSS-ILD), and to develop an exploratory diagnostic classification model for identifying pSS-ILD. In this cross-sectional study, 60 pSS patients (22 with ILD confirmed by high-resolution computed tomography [HRCT] and Warrick score, 38 without ILD) and 20 healthy controls were enrolled. Serum GDF-15 levels were measured by ELISA. Clinical data, including disease activity, laboratory parameters, and pulmonary function tests (FVC, DLCO), were systematically collected. An exploratory diagnostic classification model was developed using LASSO regression and evaluated by ROC analysis. Serum GDF-15 was significantly elevated in pSS-ILD patients compared to those without ILD and healthy controls (median 1294.1 vs. 664.33 vs. 442.93 pg/mL, both P < 0.001). In pSS-ILD patients, GDF-15 positively correlated with radiological severity (Warrick score, r = 0.465, P = 0.034) and negatively correlated with pulmonary function parameters, including FVC% (r = -0.629, P = 0.028) and DLCO% (r = -0.616, P = 0.033). LASSO regression identified GDF-15, age, lactate dehydrogenase, and IgG as key predictors. The combined model showed high apparent diagnostic performance for identifying prevalent pSS-ILD (AUC = 0.925, 95% CI: 0.850-1.000), outperforming individual clinical parameters. Serum GDF-15 is a promising biomarker candidate associated with pSS-ILD, reflecting both radiological severity and pulmonary function impairment. Integration of GDF-15 with routine clinical variables may provide a practical, non-invasive approach for identifying pSS patients with prevalent ILD, although prospective and externally validated studies are required before clinical implementation. However, the model should be regarded as exploratory and may be unstable because of the limited sample size, the low event-per-variable ratio, and the baseline age imbalance between groups; prospective, age-balanced, and externally validated studies are required before clinical implementation. Key points • Serum GDF-15 is significantly elevated in primary Sjögren's syndrome patients with interstitial lung disease and correlates with both radiological severity and pulmonary function impairment. • A multivariable exploratory diagnostic model combining GDF-15 with age, lactate dehydrogenase, and IgG showed high apparent diagnostic performance for identifying prevalent pSS-ILD. • This model may help identify pSS patients with concurrent ILD who warrant further pulmonary evaluation, but its stability should be verified in larger age-balanced cohorts with prospective external validation.

The hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene has been reported to regulate the spontaneous depolarization of sinoatrial node cells. A novel HCN4 mutation (c.2036 G>A) may lead to sick sinus syndrome. The green fluorescent protein (GFP) and either the wild-type (WT) or C679Y mutant (mut) were co-transfected into HEK293 cells to investigate the impact of the mutation on HCN4 channel function. The whole-cell patch-clamp approach was utilized to record HCN4 currents. According to electrophysiological recording, the current amplitude and density generated by mut-C679Y HCN4 channels were much lower than those generated by WT channels. HCN4 channel current activation was not significantly affected by the C679Y mutation. Because of the little current, analyzing the mut channel deactivation kinetic was challenging. Thus, we have identified a novel HCN4 gene mutation that is connected to bradycardia, left ventricular noncompaction, and diverse valve-related heart conditions.

The patient is a 28-year-old young male who was treated in November 2022. He presented back pain for over three years and was suspected of suffering from cervical spondylosis. One month before, he had been diagnosed as having pericardial effusion of unknown aetiology. An electrocardiogram examination did not reveal any abnormalities, and laboratory tests showed elevated CA125 and squamous cell carcinoma antigen. Cardiac ultrasound suggested a large lesion in the pericardial wall (Panel A1–3). Further, chest computed tomography (CT) revealed a lesion in the left ventricular lateral wall within the pericardial cavity, accompanied by slight calcification and necrotic foci (Panel B1 and 2). There were no metastases to distant organ or lymph nodes as detected by positron emission tomography (PET)-CT. The patient underwent a pericardial tumour resection to completely excise the pericardial tumour. The tumour with a specimen volume of 12 cm × 8 cm × 5 cm (Panel C). Pathological examination confirmed sarcomatoid malignant mesothelioma (Panel D1–6). Based on these results, a diagnosis of mesothelioma was made.

The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.

IMPORTANCE: Digital health applications have been shown to be effective in the management of chronic diseases with simple treatment targets. The potential clinical value of digital health applications in rheumatoid arthritis (RA) has not been well studied.OBJECTIVE: To investigate whether assessing patient-reported outcomes using digital health applications could result in disease control for patients with RA.DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter, open-label randomized clinical trial in 22 tertiary hospitals across China. Eligible participants were adult patients with RA. Participants were enrolled from November 1, 2018, to May 28, 2019, with a 12-month follow-up. The statisticians and rheumatologists who assessed disease activity were blinded. Investigators and participants were not blind to group assignment. Analysis was conducted from October 2020 to May 2022.INTERVENTIONS: Participants were randomly assigned at a 1:1 ratio (block size of 4) to a smart system of disease management group (SSDM) or a conventional care control group. Upon the completion of the 6-month parallel comparison, patients in the conventional care control group were instructed to use the SSDM application for an extension of 6 months.MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of patients with disease activity score in 28 joints using the C-reactive protein (DAS28-CRP) of 3.2 or less at month 6.RESULTS: Of 3374 participants screened, 2204 were randomized, and 2197 patients with RA (mean [SD] age, 50.5 [12.4] years; 1812 [82.5%] female) were enrolled. The study included 1099 participants in the SSDM group and 1098 participants in the control group. At month 6, the rate of patients with DAS28-CRP of 3.2 or less was 71.0% (780 of 1099 patients) in the SSDM group vs 64.5% (708 of 1098 patients) in the control group (difference between groups, 6.6%; 95% CI, 2.7% to 10.4%; P = .001). At month 12, the rate of patients with DAS28-CRP of 3.2 or less in the control group increased to a level (77.7%) that was comparable with that (78,2%) in the SSDM group (difference between groups, −0.2%; 95% CI, −3.9% to 3.4%; P = .90).CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of RA, the use of a digital health application with patient-reported outcomes was associated with an increase in disease control rate.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03715595

Background: Mitral regurgitation (MR) is a rather common valvular heart disease. The aim of this systematic review and meta-analysis was to compare the outcomes, and complications of mitral valve (MV) replacement with surgical MV repair of non-ischemic MR (NIMR) Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until October, 2020. Studies were eligible for inclusion if they included patients with MR and reported early (30-day or in-hospital) or late all-cause mortality. For each study, data on all-cause mortality and incidence of reoperation and operative complications in both groups were used to generate odds ratios (ORs) or hazard ratios (HRs). This study is registered with PROSPERO, CRD42018089608. Results: The literature search yielded 4834 studies, of which 20 studies, including a total of 21,898 patients with NIMR, were included. The pooled analysis showed that lower age, less female inclusion and incident of hypertension, significantly higher rates of diabetes and atrial fibrillation in the MV replacement group than MV repair group. No significant differences in the rates of pre-operative left ventricle ejection fraction (LVEF) and heart failure were observed between groups. The number of patients in the MV repair group was lower than in the MV replacement group. We found that there were significantly increased risks of mortality associated with replacement of MR. Moreover, the rate of re-operation and post-operative MR in the MV repair group was lower than in the MV replacement group. Conclusions: In patients with NIMR, MV repair achieves higher survival and leads to fewer complications than surgical MV replacement. In light of these results, we suggest that MV repair surgery should be a priority for NIMR patients.

Background: Mitral regurgitation (MR) is a rather common valvular heart disease. The purpose of this meta-analysis is to compare the outcomes, and complications of mitral valve replacement (MVR) with surgical mitral valve repair (MVr) of non-ischemic MR (NIMR).Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through Oct 2020. 4834 studies were reviewed, and only 20 studies enrolling a total of 21,898 patients with NIMR were included. Eligible studies were enrolling patients with MR and reporting early (30-day or in-hospital) or late all-cause mortality. For each study, data regarding all-cause mortality and incidence of reoperation and operative complications in both groups were used to generate odds ratios (ORs) or hazard ratios (HRs). Results: The pooled analysis showed that lower age, rate of women and incident of hypertension, significantly rates of diabetes and atrial fibrillation in MVR group than MVr group, no significant difference in rates of pre-operative left ventricle ejection fraction (LVEF) and heart failure. Subjects in MVr group is slightly less than MVR group. Replacement of MR has significantly increased risk of early and late mortality. Moreover, the rate of re-operation and post-operative MR in MVr group is lower than MVR group.Conclusions: In patients with NIMR, MVr procedure achieves higher survival and fewer complications than surgical MVR. Given these results, MVr surgery should be a priority for NIMR patients.

Objective: The aim at the current study was to investigate the clinical characteristics and risk factors of Raynaud’s phenomenon (RP) in patients with primary Sjögren’s syndrome (pSS). Methods: Retrospective analysis of the medical records of 333 new-onset pSS patients was performed. Demographic, clinical, and serological data were compared between individuals with and without RP. Logistic regression analysis was used to identify risk factors. Results: RP was present in 11.41% of the pSS patients. pSS-RP patients were younger (49.74±14.56 years vs. 54.46±13.20 years, p=0.04) and exhibited higher disease activity (11 [5.75–15] vs. 7 [4–12], p=0.03) than those without. The prevalence of lung involvement was significantly higher in pSS patients with RP (60.53% vs. 17.29%; pp=0.003, p=0.04), anti-RNP positive status (OR=79.41, 95% CI 12.57–501.78; pp=0.002) as prognostic factors for pSS-RP. Conclusion: The presence of RP defined a subset of pSS with a unique phenotype, manifesting as increased lung involvement and a higher frequency of anti-RNP antibodies and ACA, as well as greater disease activity. These results suggest that RP has clinical and prognostic value of pSS patients. Further prospective studies with a larger number of subjects are warranted to confirm our findings and assess the prognostic and treatment implications of RP in pSS patients. Key Points• Raynaud’s phenomenon (RP) was present in 38 (11.41%) of 333 patients with primary Sjögren’s syndrome (pSS), with patients with RP exhibiting a younger age and higher disease activity.• The presence of RP indicates a subset of pSS with a unique phenotype, with manifestations including increased lung involvement and a higher frequency of anti-RNP antibodies and anti-centromere antibodies.• Patients with pSS and RP need close follow-up and long-term observation (including assessment of microangiopathy), with specific attention paid to the possible development of clinical features of systemic sclerosis.

Liver X receptor α (LXRα) controls a set of key genes involved in cholesterol metabolism. However, the molecular mechanism of this regulation remains unknown. The regulatory role of poly(ADP-ribose) polymerase 1 (PARP1) in cholesterol metabolism in the liver was examined. Activation of PARP1 in the liver suppressed LXRα sensing and prevented upregulation of genes involved in HCD-induced cholesterol disposal. Mechanistically, LXRα was poly(ADP-ribosyl)ated by activated PARP1, which decreased DNA binding capacity of LXRα, thus preventing its recruitment to the target promoter. Intriguingly, we found that unactivated PARP1 was indispensable for LXRα transactivation and target expression. Further exploration identified unactivated PARP1 as an essential component of the LXRα-promoter complex. Taken together, the results indicate that activated PARP1 suppresses LXRα activation through poly(ADP-ribosyl)ation, while unactivated PARP1 promotes LXRα activation through physical interaction. PARP1 is a pivotal regulator of LXRα signaling and cholesterol metabolism in the liver.

Myocardial ischemia-reperfusion (IR) injury occurs when occlusive coronary artery restores blood supply after events such as myocardial infarction, stroke, cardiac arrest and resuscitation, and organ transplantation. However, the mechanisms involved are poorly understood, and effective pharmacological interventions are still lacking. A previous study demonstrated that 25-hydroxycholesterol (25-HC) contributed to lipid metabolism and cholesterol metabolism as an oxysterol molecule. We herein explored whether 25-hydroxycholesterol (25-HC) has cardioprotective properties against IR injury and explored its underlying mechanisms. 25-HC was administered before reperfusion procedure in IR injury model mice. We found that 25-HC significantly reduced the IR-induced infarct size and improved cardiac function, and this protective effect was associated with reduced phosphorylation of p38-MAPK and JNK1/2. Besides, 25-HC also inhibited the Bax/Bcl-2 ratio and the relative expression of cleaved caspase-3. Furthermore, 25-HC decreased the PARP activity, indicating that 25-HC ameliorates IR injury via the PARP pathway. The 25-HC group abolished cardioprotection in the presence of little PARP activity, suggesting that the PARP activity is essential for 25-HC to exert its effect during IR injury. Our primary study indicates that 25-HC ameliorated IR injury by inhibiting the PARP activity and decreasing myocardial apoptosis, which makes it a potential therapeutic drug in IR injury of the heart.