Osteoarthritis (OA) is a prevalent whole-joint disease that requires effective disease-modifying therapies. Intra-articular platelet-rich plasma (PRP) injections offer a minimally invasive treatment option, but face two coupled challenges: premature ex vivo activation causes rapid growth-factor release before injection, and the inflamed, protease-rich synovial microenvironment accelerates their subsequent degradation. To address these barriers, we report an injectable dual-component hyaluronic acid (HA) hydrogel depot (PRP@Gel) that combines dynamic covalent HA-based delivery with a calcium-containing matrix designed to facilitate PRP activation and sustained immunomodulation. Distinct from conventional HA/PRP hydrogels that mainly improve local retention or deliver pre-activated PRP, PRP@Gel uses a calcium-integrated AHA-Ca backbone to support gradual post-injection PRP activation within the joint cavity, thereby limiting burst release of platelet-derived factors. Sustained calcitriol release concurrently promoted a tolerogenic DC phenotype in vitro and was associated with a shift from Th17-related responses toward Treg-related features. This immune modulation was associated with reduced MMP3 and CTSK expression, which may establish a less proteolytic microenvironment for PRP-derived factors. In a rat OA model, PRP@Gel treatment improved gait symmetry and cartilage integrity. Together, these findings support an integrated strategy that coordinates PRP activation with immune modulation to sustain regenerative signaling in OA joints.

Background: Cardiac rhabdomyomas (CRs) are one of the typical phenotypes of tuberous sclerosis complex (TSC) diseases. Patients with CR could present various phenotypes and different severities. TSC1 and TSC2 are candidate genes for TSC. The genotype and phenotype relationship of the CR phenotype in TSC is unknown. Methods: TSC1 and TSC2 pathogenic and likely pathogenic variants from the HGMD, ClinVar, and LOVD databases were identified (last date: 2024.12.01). After critical exclusion criteria and pathogenicity reanalyses, statistical analyses were performed for enrichment evaluation. Results: In this study, 1250 variants of TSC1 were finally included, and 26 variants (20.8%) were reported to cause the CR phenotype. In Exon 15, 5.1% of them were CR-related (p < 0.001), and 7.1% of them were enriched in Exon 18 (p = 0.008). After adjusting by the Benjamini-Hochberg FDR method, the FDR-adjusted p values were still significant for Exon 15 (p = 0.006) and Exon 18 (p = 0.028). Considering the size of each exon, there is no significant enrichment by Poisson model analysis. We included 2690 variants of TSC2; 117 variants (4.3%) were reported to cause the CR phenotype. In Exon 41, 12% of variants were CR-related (p = 0.003). The FDR-adjusted p value was not significant for Exon 41 (p = 0.11). Considering the size of each exon, in Poisson model analysis, there are significant enrichments detected in Exon 37 (IRR = 2.72 [1.42, 5.19], p = 0.003), Exon 38 (IRR = 3.26 [1.65, 6.44], p = 0.001), and Exon 41 (IRR = 5.79 [3.11, 10.77], p < 0.001). After adjusting by the Benjamini-Hochberg FDR method, significant differences remained in these three exons. Conclusion: CR phenotypes demonstrated partial enrichment in specific exons, highlighting the importance of exon-level interpretation during genetic counseling.

Osteoarthritis (OA) is a leading cause of disability among the elderly, characterized by aberrant subchondral bone remodeling that precedes cartilage degeneration. We identify parvalbumin (Pvalb) in osteocytes as a critical mechanosensory regulator of this pathological process. Pvalb expression is significantly reduced in osteocytes from both OA patients and male murine models of the disease. Conditional deletion of Pvalb in osteocytes accelerates OA progression, whereas bone-targeted restoration of Pvalb expression mitigates disease manifestations. Mechanistically, Pvalb maintains calcium homeostasis by competing with CaMKIV for calmodulin binding. Under excessive mechanical loading, Pvalb expression is suppressed, leading to activation of the Ca²+-CaMKIV-CREB signaling pathway, increased RANKL production, and subsequent osteoclast activation and pathological bone remodeling. These findings identifies an osteocyte-mediated mechanotransduction pathway in OA pathogenesis and underscore Pvalb as a promising therapeutic target.

ObjectiveTo explore the efficacy and safety of dapagliflozin therapy in children with heart failure with reduced ejection fraction.MethodsThis was a retrospective cohort study based on electronic medical records. For the retrospective cohort study, 32 children with heart failure with reduced ejection fraction diagnosed at Shanghai Children's Medical Center and Fujian Children's Hospital from June 2021 to June 2023 and who were treated with dapagliflozin were enrolled. For pediatric patients weighing <10 kg, dapagliflozin was administered at a dosage of 0.2 mg/kg/d. Patients with a body weight ranging from 10 kg to less than 20 kg (20 > weight ≥10 kg) received dapagliflozin at a dose of 2.5 mg/d. Those weighing between 20 kg and less than 30 kg (30 > weight ≥20 kg) were prescribed dapagliflozin at 5 mg/d. For patients weighing 30 kg or more, the initial dose of dapagliflozin was 5 mg/d, which was increased to 10 mg/d after one month. 42 children treated during the same period without dapagliflozin were included as the control group. All children were treated with standard guideline-directed triple combination of ACEI/ARNI, β-blocker, and aldosterone receptor antagonist. Clinical characteristics, underlying diseases, cardiac function ratings, left ventricular ejection fraction, B-type natriuretic peptide, and blood biochemical indexes were collected. Changes in cardiac function ratings, left ventricular ejection fraction, and B-type natriuretic peptide at 24 (±2) weeks of treatment were observed; the incidence of hospitalization or death due to exacerbation of heart failure at 24 (±2) weeks of treatment was observed secondarily. Adverse medicine events such as hypoglycemia or hypotension were also observed during treatment.ResultsAmong the 32 children, 20 were male and 12 were female, aged (6.32 ± 4.00) years; weight (22.19 ± 12.66) kg. The underlying diseases included dilated cardiomyopathy in 25 cases, dilated cardiomyopathy combined with complete left bundle branch block in two cases, postoperative congenital heart disease in four cases, and atrial tachycardia in one case. At 24 (±2) weeks of treatment, left ventricular ejection fraction level significantly increased compared with baseline (P < 0.001); B-type natriuretic peptide decreased (P < 0.001); and New York Heart Association (NYHA) cardiac function ratings improved significantly (P = 0.034). Compared with the control group, children in the dapagliflozin group showed greater improvement in left ventricular ejection fraction (P = 0.032) and NYHA cardiac function rating (P = 0.038), whereas no significant difference was observed in BNP levels (P = 0.071). Three children developed urinary tract infection during the administration of the medication, and three children developed hypotension, while no other adverse reactions, such as hypoglycemia or hepatic or renal function impairment, were observed.ConclusionDapagliflozin was associated with improvements in left ventricular ejection fraction, BNP, and NYHA cardiac function classification in children with heart failure with reduced ejection fraction. No hospitalization or death due to the deterioration of heart failure and no serious adverse reactions were observed. The treatment was generally well tolerated, and the weight-stratified dosing strategy showed acceptable short-term safety.

Background The interplay between programmed cell death and mitochondrial dysfunction is a central mechanism in Kawasaki disease pathogenesis, yet the specific molecular connectors within this network are poorly defined. This study aimed to identify and validate integrated biomarkers that bridge these processes, offering new diagnostic and mechanistic insights.Methods Using the GSE73461 dataset as a training set, we identified Kawasaki disease-related differentially expressed genes. These were intersected with curated programmed cell death-related and mitochondrial-related gene sets to obtain candidates. Subtype-specific analysis was performed to clarify which programmed cell death processes were most closely linked to mitochondrial dysfunction. A protein-protein interaction network was constructed, and hub genes were screened using multiple algorithms. Biomarker selection was refined via two machine learning models. Diagnostic performance was evaluated using the independent GSE68004 validation set, receiver operating characteristic analysis, and a composite nomogram. Immune infiltration, functional enrichment, regulatory network construction, drug prediction, and molecular docking were also conducted. Finally, biomarker expression was validated in clinical blood samples using reverse transcription quantitative polymerase chain reaction.Results We identified 63 candidate genes. Five biomarkers-CD177, Matrix Metallopeptidase 9, Nuclear Factor Erythroid 2, Colony Stimulating Factor 3 Receptor, and Suppressor Of Cytokine Signaling 3-were consistently upregulated in Kawasaki disease and showed high diagnostic accuracy (area under the curve >0.94 in both datasets). These biomarkers are functionally anchored in a network where specific programmed cell death subtypes, strongly correlated with mitochondrial genes, converge on inflammatory pathways. A diagnostic nomogram integrating all five biomarkers achieved an area under the curve of 0.986. Clinical validation confirmed significant upregulation of CD177, Matrix Metallopeptidase 9, and Suppressor Of Cytokine Signaling 3, while Nuclear Factor Erythroid 2 and Colony Stimulating Factor 3 Receptor exhibited no significant differential expression. All five biomarkers were enriched in the Fc gamma receptor-mediated phagocytosis pathway and correlated cohesively with key immune cells. Decitabine and Ibuprofen were highlighted as potential therapeutic candidates.Conclusion This study defines a novel five-biomarker panel that functionally links mitochondrial dysfunction, dysregulated programmed cell death, and immune activation in Kawasaki disease, providing an integrated, mechanism-based framework for improving diagnosis and guiding future targeted therapies.

BACKGROUND:A sustained dosage of VEGFA (vascular endothelial growth factor A) is crucial for angiogenesis in both homeostasis and cardiovascular diseases. Start codon CUG-initiated alternative translation is a conserved mechanism for producing mature VEGFA. Genetic surveys have identified stop-gained variants predicted to prematurely terminate CUG-initiated translation without affecting start codon ATG-initiated translation. However, the impacts of these variants on the vasculature in steady-state and disease conditions remain unknown. METHODS:Using CRISPR/Cas9 genome editing, we established the VegfaQ150X/Q150 allele (Q150X), a mouse genetic model that mimics the human VEGFA stop-gained variant. The effects of this variant were tested in both adult homeostatic conditions and the acute myocardial infarction (MI) model. We analyzed and quantified cardiac vasculature structure using immunofluorescence and light-sheet imaging. Furthermore, we characterized cellular heterogeneity, cell-cell interactions, and gene regulation using single-nucleus RNA sequencing, as well as cell type-specific transcriptomics and epigenomics. RESULTS:Homozygous mice carrying the stop-gained variant were viable. VEGFA dosage was reduced to 70% in the Q150X homeostatic heart, with no significant alteration in cardiac function or vasculature. In the MI model, VEGFA dosage in Q150X was reduced to about 40% within the first week post-infarction, leading to functional deterioration in the post-MI hearts. Significant changes in cellular composition were observed 3 days post-MI. In particular, endothelial cells in Q150X diverged into a state that showed a higher level of hypoxia stress, an elevated inflammatory response, and increased extracellular matrix secretion. In addition, we observed an increase in Nppb+ stressed cardiomyocytes in both 3 days post-MI and homeostasis. Finally, proinflammatory macrophages, neutrophils, and Cd8+T cells were enriched in the ischemic zone of Q150X hearts. CONCLUSIONS:CUG-initiated translation contributes significantly to the production of mature VEGFA in ischemic hearts. VEGFA dosage is critical in determining the cellular microenvironment during ischemic injury.

Background:Bone and joint infections (BJI) are a significant complication after arthroplasty and fracture fixation, particularly challenging in patients with type 2 diabetes mellitus (T2DM) and obesity. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has shown efficacy in managing T2DM and obesity. However, its impact on BJI risk and neutrophil function remains unclear. To investigate whether preoperative semaglutide treatment (1) reduces the risk of BJI in diabetic and obese mice undergoing intra-articular implants, and (2) outperforms insulin in restoring neutrophil function to mitigate implant-related infection.Methods:A C57BL/6 mouse model of T2DM/obesity was induced using a high-fat diet (HFD) for 12 weeks. Mice received preoperative insulin or semaglutide therapy for 1-28 days. BJI risk was assessed using an intra-articular-implant model challenged with Staphylococcus aureus or Escherichia coli. The neutrophil function was evaluated through bactericidal activity, superoxide production, and migration ability.Results:Semaglutide treatment led to a significant and sustained reduction in body weight and improved glucose tolerance in HFD mice. Both insulin and semaglutide therapies significantly reduced BJI risk, with semaglutide showing a more pronounced effect over time. Semaglutide therapy also enhanced neutrophil bactericidal activity, superoxide production, and migration ability compared to insulin therapy.Conclusions:Preoperative semaglutide treatment effectively reduces BJI risk and improves neutrophil function in diabetic and obese mouse models. These findings suggest that semaglutide may be a promising pharmacological intervention to mitigate infection risk in orthopedic patients with T2DM or obesity.

Aims:Cystic lesions are strongly associated with the pathogenesis and selection of treatment strategies in osteoarthritis (OA) and osteonecrosis of the femoral head (ONFH). However, the differences in cystic lesions arising from these two diseases are not fully understood. This study aimed to delineate the variations in cyst characteristics in the femoral heads of patients with OA and ONFH. Methods:A total of 45 patients with OA and 105 patients with ONFH who underwent total hip arthroplasty (THA) between September 2014 and December 2021 were recruited in the study. The 3D distribution, microstructure, and histological characteristics of cystic lesions were comprehensively analyzed. Comparative assessments of the microstructural, histomorphometric, and histopathological properties of cystic lesions between OA and ONFH were performed, using micro-CT, decalcified and undecalcified bone histomorphology, and scanning electron microscopy (SEM). Results:In comparison to ONFH, cystic lesions in OA exhibited a smaller volume and a denser distribution. Despite a common prevalence in the anterior hemisphere in both conditions, ONFH cysts were predominantly located laterally, whereas OA cysts were found mainly medially. In OA, the trabecular bone surrounding the cystic lesions exhibited a more sclerotic microarchitecture, with an increase in bone formation and a decrease in bone resorption at the remodelling level. Histologically, cystic lesions in ONFH demonstrated a higher degree of angiogenesis compared to those in OA. Conclusion:While cystic lesions in both OA and ONFH were predominantly located in the anterior hemisphere, they exhibited different distribution and involvement characteristics, microstructure and bone remodelling properties, as well as histopathological features.

Introduction The infrapatellar fat pad and synovium are the sites of immune cell infiltration and the origin of proinflammation. Studies have shown that Hoffa’s synovitis may be a sign of early-stage osteoarthritis (OA). However, there have been no effective interventions specifically for Hoffa’s synovitis.Methods and analysis We will conduct a multicentre, multi-blind (participant, physician, outcome assessor and data analyst blinded) randomised controlled trial to compare the effectiveness of an intra-infrapatellar fat glucocorticoid versus an intra-articular injection for Hoffa’s synovitis in patients with knee OA. We will recruit 236 knee OA patients with Hoffa’s synovitis at outpatient clinics in three centres. We will randomly allocate them to two groups in a 1:1 ratio. One group will receive ultrasound-guided injection of 40 mg (1 mL) triamcinolone acetonide into the infrapatellar fat pad; the other group will receive ultrasound-guided injection of 40 mg (1 mL) triamcinolone acetonide into the knee joint cavity. All patients will be followed up at 2, 4, 8, 12 and 24 weeks after the injection. Primary outcomes are (1) Hoffa’s synovitis improvement rate, measured with the MRI Osteoarthritis Knee Score system (superiority outcome) at 24 weeks and (2) pain intensity, measured with the Western Ontario and McMasters University Osteoarthritis Index (WOMAC) at 2 weeks post-injection. Secondary outcomes include Hoffa’s synovitis score at 2 weeks post-injection, pain intensity with the numerical rating scale, WOMAC questionnaire score improvements (function, joint stiffness and total score), improvement rates in effusion synovitis at 2 and 24 weeks, articular cartilage thickness changes at 2 and 24 weeks, Intermittent and Constant Osteoarthritis Pain score, quality of life measured with the EuroQol-5D, OARSI-OMERACT response indicators, co-interventions and side effects at 2, 4, 8, 12 and 24 weeks.Ethics and dissemination Ethical approval has been granted by the Medical Ethics Committee of the Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (2023–178). Written informed consent will be obtained from all patients prior to data collection. The findings of this research will be shared through presentations at academic conferences and publications in peer-reviewed journals.Trial registration number ChiCTR2400080474.

ObjectiveEarly assessment and intervention of Acquired Immune Deficiency Syndrome (AIDS) patients at high risk of mortality is critical. This study aims to develop an optimally performing mortality risk prediction model for AIDS patients with comorbid AIDS-related diseases or symptoms to facilitate early intervention.MethodsThe study included 478 first-time hospital-admitted AIDS patients with related diseases or symptoms. Eight predictors were screened using lasso regression, followed by building eight models and using SHAP values (Shapley’s additive explanatory values) to identify key features in the best models. The accuracy and discriminatory power of model predictions were assessed using variable importance plots, receiver operating characteristic curves, calibration curves, and confusion matrices. Clinical benefits were evaluated through decision-curve analyses, and validation was performed with an external set of 48 patients.ResultsLasso regression identified eight predictors, including hemoglobin, infection pathway, Sulfamethoxazole-Trimethoprim, expectoration, headache, persistent diarrhea, Pneumocystis jirovecii pneumonia, and bacterial pneumonia. The optimal model, XGBoost, yielded an Area Under Curve (AUC) of 0.832, a sensitivity of 0.703, and a specificity of 0.799 in the training set. In the test set, the AUC was 0.729, the sensitivity was 0.717, and the specificity was 0.636. In the external validation set, the AUC was 0.873, the sensitivity was 0.852, and the specificity was 0.762. Furthermore, the calibration curves showed a high degree of fit, and the DCA curves demonstrated the overall high clinical utility of the model.ConclusionIn this study, an XGBoost-based mortality risk prediction model is proposed, which can effectively predict the mortality risk of patients with co-morbid AIDS-related diseases or symptomatic AIDS, providing a new reference for clinical decision-making.

Bone defects are a major clinical challenge, primarily owing to the limited self-healing capacity of bones and the high risk of complications associated with conventional treatment strategies. Traditional tissue engineering approaches typically rely on intramembranous ossification for bone repair however, this method often yields suboptimal results. In this study, we found that chondrocyte sheets derived from human induced pluripotent stem cells (iPSCs) can be activated through immune stimulation to initiate endochondral ossification in vivo. Based on these findings, we hypothesized that cartilage-based materials might be more effective in inducing osteogenesis during bone defect repair. Human platelet lysate (HPL) is a cost-effective and readily available source of bioactive molecules. It is rich in various growth factors and functional proteins and has shown significant application potential in regenerative medicine. In this study, we developed a novel method for preparing iPSC-derived chondrocyte sheets augmented with HPL (iCDCHs). Experimental results revealed that HPL treatment significantly enhanced endochondral ossification within chondrocyte sheets and accelerated bone regeneration. Compared with allogeneic bone grafts, iCDCHs resulted in improved bone repair outcomes, with notably lower immunogenicity. Further analysis revealed that chondrocyte sheets promoted M2 macrophage polarization by activating the PI3K/Akt signaling pathway, thereby generating various pro-regenerative metabolic factors and establishing a microenvironment conducive to effective bone repair. These findings suggest that iPSC-derived chondrocyte sheets hold promise in the repair of bone defects and serve as a valuable alternative to allogeneic bone grafts in tissue engineering.

Viral myocarditis (MC) is caused by Coxsackie virus B3 (CVB3)-induced cardiomyocyte apoptosis and inflammation, and changes in miRNA and lncRNA are linked to cardiac remodeling. The long non-coding RNA XIST (XIST) has been identified as a regulator in various pathological processes in heart diseases, but its role in CVB3-induced MC is not well understood. This research aimed to evaluate the impact that XIST has on CVB3-induced MC as well as the mechanism behind this effect. XIST expression in CVB3-exposed H9c2 cells (H9c2 cells) was evaluated by qRT-PCR. In CVB3-exposed H9c2 cells, reactive oxygen species production, inflammatory mediators, and apoptosis were experimentally observed. An investigation into and confirmation of the existence of an interaction involving XIST, miR-140-3p, and RIPK1 were carried out. The findings showed that CVB3 induced upregulation of XIST in H9c2 cells. However, XIST knockdown reduced oxidative stress, inflammation, and apoptosis of CVB3-exposed H9c2 cells. XIST was specifically bound to miR-140-3p, and there was mutual negative regulation between the two. Moreover, XIST downregulated RIPK1, which was mediated by miR-140-3p. The study suggests that downregulating XIST can alleviate inflammatory injury in CVB3-exposed H9c2 cells through the miR-140-3p/RIPK1 axis. These findings provide novel insights into the underlying mechanisms of MC.

ObjectivesSPARCL1 is a matricellular protein that mediates the cell–matrix interactions and participates in physiological processes such as cell adhesion, differentiation and proliferation. However, its role in chondrocyte and osteoarthritis (OA) progression has not been fully characterized. We aimed to evaluate the effects of SPARCL1 on OA through in vitro and in vivo experiments.MethodsExpression of SPARCL1 was examined in 55 paired human OA samples. Effects of Sparcl1 on chondrocytes were identified in vitro. Intra-articular injection was performed in an anterior cruciate ligament transection (ACLT) mouse model. Alterations of SPARCL1-mediated signaling pathway were identified by RNA-seq analysis. qPCR and western-blot were used to demonstrate the potential signaling pathway.ResultsSPARCL1 expression in the OA cartilage was increased compared with undamaged cartilage. Recombinant Sparcl1 protein induced extracellular matrix degradation in chondrocytes. Furthermore, intra-articular injection of recombinant Sparcl1 protein in ACLT mice could promote OA pathogenesis. Mechanistically, Sparcl1 activated TNF/NF-κB pathway and consequently led to increased transcription of inflammatory factors and catabolism genes of cartilage, which could be reversed by NF-κB inhibitor BAY 11–7082.ConclusionSPARCL1 could promote extracellular matrix degradation and inflammatory response to accelerate OA progression via TNF/NF-κB pathway.The translational potential of this articleThe current research could help to gain further insights into the underlying molecular mechanism in OA development, and provides a biological rationale for the use of SPARCL1 as a potential therapeutic target of OA.

Objective:To investigate the clinical characteristics of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants, and the impact factors of duration of cycle threshold (Ct) values turning to ≥35 detected by nucleotide test.Methods:Children aged 0 to 14 years with clinical symptoms of Omicron variants infection who admitted to designated hospital in Shanghai City (Renji Hospital, South Branch, Shanghai Jiao Tong University School of Medicine) from April 7 to June 2, 2022 were enrolled. The daily nasopharyngeal swab specimens were used for SARS-CoV-2 nucleic acid detecting by polymerase chain reaction and the results were expressed as Ct values. The T Ct≥ x was defined as from the symptom onset or first positive nucleic acid test results (the earlier data) to Ct≥ x of the open reading frame 1ab ( ORF1 ab) gene, which was the time duration from the initial to a specific Ct value.Clinical data were collected, including age, sex, vaccination and comorbidities.Cox model was performed to analyzed the impact factors of T Ct≥35. Results:A total of 871 pediatric cases with a median age of two years (ranging from one month to 14 years old) were included. Among them, 474 cases (54.4%) were male, and 89 cases (10.2%) had underlying diseases including congenital heart disease, solid tumors and epilepsy. There were 572(65.7%) mild cases, 298(34.2%) common cases, one (0.1%) severe case and no critical cases or deaths. The T Ct≥35 was 12(10, 14) days. Cox model indicated that compared to children aged one to 12 months, children aged 37 to 84 months and 85 to 168 months had shorter T Ct≥35 (hazard ratio ( HR)=1.55 and 1.84, respectively, both P<0.001). After adjusted with age, comparing to unvaccinated patients, patients with one or two shots vaccine had shorter T Ct≥35 (adjected hazard ratio (a HR)=1.49, P=0.011), and common patients had longer T Ct≥35 than mild patients (a HR=0.78, P=0.002), and patients with comorbidities had longer T Ct≥35than patients without comorbidities (a HR=0.38, P<0.001).The duration of T Ct≥28, T Ct≥30, T Ct≥33 and T Ct≥35 in children without underlying diseases were 7(6, 9) d, 9(7, 10) d, 10(8, 11) d and 12(10, 14) d, respectively. Conclusions:Age, vaccination, disease severity and underlying diseases could affect the duration of SARS-CoV-2 nucleotide turning to negative (Ct value≥35) in children infected with Omicron variants.

1例主诉为动脉导管结扎术后4年，活动后乏力2个月的13岁患儿就诊于上海儿童医学中心心内科，超声心动图诊断为动脉导管结扎术后少量残余分流、重度肺动脉高压。经导管在动脉导管结扎处植入7 mm×18 mm 支架完成Potts分流术，3个月后再予球囊进一步扩张支架增加右向左分流量。随访4年患儿运动耐量改善，无晕厥发生。

Background:The management of LT patients during COVID-19 pandemic is important. Immunosuppressants (IS) are key therapy agents after liver transplant. Different ISs have different side effects. Calcineurin inhibitor (CNI) may lead to metabolic acidosis while mycophenolate mofetil (MMF) showed rare nephrotoxicity. We report a post-liver transplant girl who was infected with SARS-CoV-2, developing a severe mixed acidosis 3 months after the transplantation. Her acidosis was improved after withdrawing of MMF, leading the suspicion that acidosis maybe a rare side effect of MMF.Case presentation:A girl was admitted to our hospital due to SARS-CoV-2 infection, 3 months before admission the patient received LT due to Niemann-Pick disease (NPD). During hospitalization, blood gas analysis showed severe mixed acidosis. To relieve mixed acidosis, the patient was given oral rehydration salt and liquid replacement therapy. Considering that immunosuppressants may cause metabolic acidosis, dose of CsA was decreased and MMF was discontinued.Results:However, liquid replacement therapy and decreased CsA dose cannot improve the condition. As an attempt, MMF was discontinued, and 3 days later, the girl's acidosis was relieved, the latest blood gas analysis was normal with the original dose of CsA and no use of MMF or other IS. In addition, we used Naranjo Scale to see if adverse drug reactions (ADRs) existed. The final score was 6 which means MMF contributes to acidosis probably.Conclusion:The girl's mixed acidosis cannot be explained by Niemann-Pick disease and SARS-CoV-2 infection. CNIs could cause metabolic acidosis but declining the dose of CsA didn't improve her acidosis while withdrawing MMF showed a good effect. Together with the Naranjo Scale result, we suspect that acidosis maybe a rare side effect of MMF.

Objective Obesity is a risk factor for knee osteoarthritis (KOA) development and progression. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity. However, whether KOA patients can benefit from GLP-1RA therapies has not been sufficiently investigated, especially in the long term. Methods The Shanghai Osteoarthritis Cohort study is a prospective, observational, multicentre study of >40 000 adults with clinically diagnosed osteoarthritis aged >45 years in Shanghai. We identified all KOA participants with comorbid T2DM enrolled from 1 January 2011 to 1 January 2017. Primary outcome was incidence of knee surgery after enrolment. Secondary outcomes included pain-relieving medication use, number of intra-articular therapies, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and medial femorotibial joint cartilage thickness. To evaluate the effects of GLP-1RA, we performed before-and-after comparison and comparison with participants who had no GLP-1RA exposure. Results For an intergroup comparison (non-GLP-1RA vs GLP-1RA), more weight loss (adjusted mean difference in weight change from baseline −7.29 kg (95% CI −8.07 to −6.50 kg), p<0.001) and lower incidence of knee surgery (93/1574 (5.9%) vs 4/233 (1.7%), adjusted p=0.014) were observed in the GLP-1RA group. Statistically significant differences in mean change from baseline for the WOMAC total and pain subscale scores were observed (adjusted mean difference in WOMAC total score −1.46 (95% CI −2.84 to −0.08), p=0.038; adjusted mean difference in WOMAC pain subscore −3.37 (95% CI −5.79 to −0.94), p=0.007). Cartilage-loss velocity of the medial femorotibial joint was significantly lower in the GLP-1RA group postadjustment for baseline characteristics (adjusted mean difference −0.02 mm (95% CI −0.03 to −0.002 mm), p=0.004). For the before-and-after comparison within the GLP-1RA group, we observed a significant decrease of symptom-relieving medication consumption and cartilage loss velocity of medial femorotibial joint (after-treatment vs before-treatment: −0.03±0.05 vs −0.05±0.07 mm/year, p<0.001). The association between GLP-1RA exposure and decreased incidence of knee surgery was mediated by weight reduction (mediation proportion: 32.1%), instead of glycaemic control (too small to calculate). Conclusion With sufficient treatment duration, GLP-1RA therapies might be disease-modifying for KOA patients with comorbid T2DM, possibly mediated by weight loss. Further investigation is needed to elucidate effects of GLP-1RA on disease process, joint structure and patient-reported outcomes of osteoarthritis.

An ideal implant needs to have the ability to coordinate the foreign body response and tissue regeneration. Here, Hydrogenated-silicon nanosheets (H-Si NSs) with favorable biodegradability are integrated and functionalized into a β-tricalcium phosphate scaffold (H-Si TCP) for bone defect healing. H-Si TCP can greatly improve bone regeneration through osteoimmunomodulation-guided biodegradation in vivo. The spatiotemporal regulation of degradation products replenishes sufficient nutrients step by step for the entire process of bone repair. Extracellular and intracellular reactive oxygen species (ROS) are first downregulated by reaction with H-Si NSs, followed by marked M2 polarization, remodeling the micro-environment timely for immune-bone regeneration. The release of primary reaction products awakened bone marrow mesenchymal stem cells (BMSCs), which are converted into osteoblasts anchored on scaffolds. Subsequently, biomineralization is promoted by the final degradation products. The intrinsic ROS-responsive, immunoregulatory, and osteo-promotive capability of 2D H-Si NSs makes such composite H-Si TCP scaffold a highly potential alternative for the treatment of critical bone defect.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first confirmed in November 2021 in South Africa[1] and is more transmissible than other sub-variants.[2] The influence of Omicron in children has been recognized with increased hospital admission rate than Delta wave.[3,4] But severe clinical outcomes and comorbidity of Omicron are less than Delta in children.[5] Hospitalized children during the Omicron period were more likely to be younger than that in the pre-Omicron period.[6] Children aged 0 to 3 years were not eligible for coronavirus disease 2019 (COVID-19) vaccination and accounted for >60% of hospitalized pediatric cases in the current wave of SARS-CoV-2 Omicron (BA.2) variant infection in Shanghai, China since March 2022.[7] A study suggested that younger children may be more likely to transmit SARS-CoV-2 infection than older children, and the highest odds of transmission were observed for children aged 0 to 3 years.[8] However, the dynamics of viral load and required isolation and quarantine time in infected children are inconclusive. We hypothesize children shed viruses longer than adults. As such, we performed this prospective viral load comparison study. The result is expected to guide quarantine time and optimal frequency of reverse transcription-quantitative polymerase chain reaction tests for SARS-CoV-2 infected children. Study design, setting, and patients’ This observational cohort study was conducted in a dedicated medical center for admitting COVID-19 infected children and adults with 890 beds, of which 470 were for children aged 0 to 14 years and their companion parents. All medical caregivers including pediatricians and nurses were deployed from three children's hospitals and one general hospital in Shanghai. Infected children aged 0 to 3 years and their 1:1 matched infected parents admitted from April 12 to 30, 2022, were eligible for the study. In the matching process, most families have one kid and one parent. For those children accompanied by two parents, we chose the same-gender parent with the child. No parent took care of more than one child. If either the child or the parent had underlying diseases, both were excluded. Clinical data of age, gender, symptoms, severity of the disease, and vaccination were retrieved from medical records. Virus load kinetics and the management of COVID-19 infection Reverse transcription-polymerase chain reaction (RT-PCR) tests provide semiquantitative results in the form of cycle threshold (Ct) values, which are inversely correlated with viral loads and are useful in determining the need for isolation and quarantine.[9]ORF1ab gene of the SARS-CoV-2 genome was detected every other day in all recruited cases. Nasal swab specimens were collected by standard procedures. Diagnosis and treatment of COVID-19 infection were based on the universal Chinese national domestic guidelines.[10] All samples with a Ct <35 were recognized as active COVID-19 infections. Patients with two consecutive Ct values >35 with intervals of >24 h are eligible for de-isolation. The dynamics of the Ct value and the time interval (days requiring isolation, [DRI]) between the onset of symptoms and the first Ct value of >35 were compared between children and their parents.[11] This study was approved by the institutional review board of the Children's Hospital of Fudan University (No. 2022–82) and gained informed consent from the parents. Categorical variables were expressed as n (%) and compared using the Chi-squared test or Fisher's exact test. Continuous variables were expressed as mean ± standard deviation or median (interquartile range). The Kaplan–Meier survival curve was drawn in the R software (version 4.1) to reflect the change in the probability of positive PCR tests between the two groups. The log rank was used to test the difference in the survival curves. We used local polynomial regression fitting to get the trend curve with a 95% confidence interval. Analysis of variance, t-test, and Fisher's exact test with adjustment for multiple testing using the false discovery rate method in the R version 4.1. Recruited children and parents We enrolled 203 children and 203 matched parents [Supplementary Figure 1, https://links.lww.com/CM9/B154]. The basic clinical characteristics of children and parents were demonstrated in Supplementary Table 1, https://links.lww.com/CM9/B154. For both children and parents, fever was the dominant phenotype (97.5% vs. 78.8%) followed by cough (63.1% vs. 80.8%). Children had a significantly higher rate of vomiting than parents (15.8% vs. 6.9%; P = 0.022). All children were mildly-to-moderately ill. No children were vaccinated. Of 203 parents, 85 (41.9%), 14 (6.9%), 61 (30.0%), and 43 (21.1%) received no vaccine or 1, 2, and 3 doses of inactivated SARS-CoV-2 vaccine. Virus load kinetics Chronological Ct value and DRI analyses in children and parents were demonstrated in Figure 1. Ct values were significantly lower in children compared with those in their parents from day 4 to day 14 after the onset of symptoms and therefore with higher quantities of viral RNA [Figure 1A].Figure 1: (A) Chronological Ct value and DRI analyses in children aged 0 to 3 years and their parents. The upper panel of the scatter plot shows ORF1ab gene Ct values in children (dark cyan) and parents (orange) after the onset of symptoms. The lines show the fitting curve by polynomial regression. The 95% CI of the regression curve is displayed as shaded confidence bands. The lower panel of the scatter plot showed the Ct value difference between children and matched parents (blue). The lines show the fitting curve by polynomial regression. The 95% CI of the regression curve is displayed as shaded confidence bands (pink). From day 4 to day 14, the deviation of Ct value between parents and children had a significant difference by paired Student's t-test (adjusted P < 0.05). The adjustment for testing using the FDR method. (B) Time gap from symptom onset to negative PCR test results in children and parents. Ct trajectory of infected children (dark cyan) and 1:1 matched parents (orange). CI: Confidence interval; Ct: Cycle threshold; DRI: Days requiring isolation; FDR: False discovery rate; PCR: Polymerase chain reaction.Virus shedding time comparisons between groups DRI in children was significantly longer than that in their parents (13.4 ± 2.7 days vs. 11.4 ± 3.0 days, P < 0.001) [Figure 1B]. Subgroup analyses demonstrated that DRI was significantly longer in mothers than that in fathers, unvaccinated than vaccinated parents, and children than unvaccinated parents [Table 1]. Table 1 - Virus shedding time (DRI) of subgroups. Group DRI P value Children Male vs. female 13.5 ± 2.5 vs. 13.3 ± 3.3 0.575 Mild vs. moderate 13.4 ± 2.7 vs. 13.3 ± 3.2 0.894 Age at 0–6 months vs. 6–12 months 13.8 ± 2.3 vs. 13.5 ± 2.7 0.668 Age at 6–12 months vs. 12–36 months 13.5 ± 2.7 vs. 13.2 ± 2.9 0.462 Age at 0–6 months vs. 12–36 months 13.8 ± 2.3 vs. 13.2 ± 2.9 0.961 Adults Fathers vs. mothers 10.2 ± 2.3 vs. 11.4 ± 3.0 0.019 Mild vs. moderate 11.1 ± 2.9 vs. NA NA Vaccinated 0 vs. 1/2 12.3 ± 3.5 vs. 11.0 ± 2.3 0.015 Vaccinated 0 vs. 3 12.3 ± 3.5 vs. 10.1 ± 2.7 <0.001 Vaccinated 1/2 vs. 3 11.0 ± 2.3 vs. 10.1 ± 2.7 0.551 Children vs. adults 13.4 ± 2.7 vs. 11.4 ± 3.0 <0.001 Children vs. unvaccinated adults 13.4 ± 2.7 vs. 12.3 ± 3.5 <0.001 Data are shown as mean ± standard deviation; DRI: Days requiring isolation; NA: Not applicable. In this study, we found that it took longer to reach a Ct value of >35 for young children compared with adults, which implied that children shed viruses much longer and required longer quarantine time. In the pandemic, children could be a source of infection for family members, especially the elderly with comorbidities predisposed to the severe form of COVID-19 infection.[12,13] Therefore, for children aged 0 to 3 years, a strict quarantine strategy and particular contact caution for the elderly in the same family could potentially minimize the risk of secondary household transmission. In our study, we used the Ct value detected by RT-PCR as a proxy of viral load. The exact duration of COVID-19 patients being infectious is unclear and is likely dependent on many factors, but in particular, the individual's disease severity, the viral load, and the patient's immune status. A positive viral culture has been correlated with viral loads quantified by RT-PCR. The likelihood of a positive viral culture decreases with increasing Ct values.[14] In one study, no positive culture of SARS-CoV-2 from samples was detected when Ct was 28 to 30.[15] In other studies, the negative culture threshold of Ct values was >24 or >34.[14,16] Currently, Ct > 35 is used as the criteria for discharge in China, which seems safe in preventing subsequent community transmission by infected patients. As most SARS-CoV-2 Omicron variant-infected children were mild and moderate, home quarantine may be suitable without overwhelming hospital capacities in the pandemic. Based on our data, the optimal time for PCR test in infected children aged 0 to 3 years can be performed on the 11th to 16th (13.4 ± 2.7) day after the onset of symptoms with the best chance to get a negative result. This strategy can be cost-effective and significantly reduce the frequency of PCR tests in children. Due to >30 mutations on the spike protein, the SARS-CoV-2 Omicron variant demonstrates a greater breakthrough against vaccine-induced immunity as compared to the delta. However, the administration of COVID-19 vaccines, no matter the mRNA vaccine, inactivated vaccine, or other forms of vaccines, is still the most effective public health strategy for preventing severe forms of COVID-19. Additionally, our study found that the duration of shedding viruses in vaccinated adults was much shorter than that in unvaccinated counterparts, which gives extra evidence for vaccination in all eligible populations. In conclusion, based on our comparison study of children and parents, we found that children aged 0 to 3 years tend to shed virus longer than their parents, which implies a longer quarantine duration for young children is needed and the optimal PCR testing time for detecting a negative result with the purpose of de-isolation is around 2 weeks. For all eligible populations, vaccination is strongly recommended, not only for preventing infection but also for shortening viral shedding time in vaccine-breakthrough infections. Funding This study was funded by the National Key Research and Development Program of China (Nos. 2021YFC2701800 and 2021YFC2701801) and the Shanghai Municipal Science and Technology Major Project (No. ZD2021CY001). Conflicts of interest None.