Cardiovascular mortality risk in patients with ovarian cancer: a population-based study.

OBJECTIVES: Ovarian cancer (OC) can occur at different ages and is affected by a variety of factors. In order to evaluate the risk of cardiovascular mortality in patients with ovarian cancer, we included influencing factors including age, histological type, surgical method, chemotherapy, whether distant metastasis, race and developed a nomogram to evaluate the ability to predict occurrence. At present, we have not found any correlation studies on cardiovascular death events in patients with ovarian cancer. This study was designed to provide targeted measures for effective prevention of cardiovascular death in patients with ovarian cancer. METHODS: Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of cardiovascular diseases on overall survival (OS) and ovarian cancer-specific survival (OCSS). We compared multiple groups including clinical, demographic, therapeutic characteristics and histological types. Cox risk regression analysis, Kaplan-Meier survival curves, and propensity score matching were employed for analyzing the data. RESULTS: A total of 88,653 ovarian cancer patients were collected, of which 2,282 (2.57%) patients died due to cardiovascular-related diseases. Age, chemotherapy and whether satisfactory cytoreduction surgery is still the most important factors affecting the prognosis of ovarian cancer patients, while different histological types, diagnosis time, and race also have a certain impact on the prognosis. The newly developed nomogram model showed excellent predictive performance, with a C-index of 0.759 (95%CI: 0.757-0.761) for the group. Elderly patients with ovarian cancer are still a high-risk group for cardiovascular death [HR: 21.07 (95%CI: 5.21-85.30), p < 0.001]. The calibration curve showed good agreement from predicted survival probabilities to actual observations. CONCLUSION: This study found that age, histology, surgery, race, chemotherapy, and tumor metastasis are independent prognostic factors for cardiovascular death in patients with ovarian cancer. The nomogram-based model can accurately predict the OS of ovarian cancer patients. It is expected to inform clinical decision-making and help develop targeted treatment strategies for this population.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases.

BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.

Regulating cathode surface hydroxyl chemistry enables superior potassium storage.

Potassium vanadium fluorophosphate (KVPO4F) is regarded as a promising cathode candidate for potassium-ion batteries due to its high working voltage and satisfactory theoretical capacity. However, the usage of electrochemically inactive binders and redundant current collectors typically results in inferior electrochemical performance and low energy density, thus implying the important role of rational electrode structure design. Herein, we have reported a scalable and cost-effective synthesis of a cellulose-derived KVPO4F self-supporting electrode, which features a special surface hydroxyl chemistry, three-dimensional porous and conductive framework, as well as super flexible and stable architecture. The cellulose not only serves as a flexible substrate, a pore-forming agent, and a versatile binder for KVPO4F/conductive carbon but also enhances the K-ion migration ability. Benefiting from the special hydroxyl chemistry-induced storage mechanism and electrode structural stability, the flexible freestanding KVPO4F cathode exhibits high-rate performance (53.0% capacity retention with current densities increased 50-fold, from 0.2 C to 10 C) and impressive cycling stability (capacity retention up to 74.9% can be achieved over 1,000 cycles at a rate of 5 C). Such electrode design and surface engineering strategies, along with a deeper understanding of potassium storage mechanisms, provide invaluable guidance for better electrode design to boost the performance of potassium-ion energy storage systems.

Efficacy and safety of multi-target therapy in children with lupus nephritis.

BACKGROUND: To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN). METHODS: In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed. RESULTS: The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy. CONCLUSIONS: Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN. IMPACT: The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.

miR-4433a-3p promotes granulosa cell apoptosis by targeting peroxisome proliferator-activated receptor alpha and inducing immune cell infiltration in polycystic ovarian syndrome.

BACKGROUND: Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various ovulatory obstacles, eventually resulting in the development of ovarian disorders such as polycystic ovarian syndrome (PCOS). Apoptosis and dysregulated miRNA expression in GCs are manifestations of PCOS. miR-4433a-3p has been reported to be involved in apoptosis. However, there is no study reporting the roles of miR-4433a-3p in GC apoptosis and PCOS progression. METHODS: miR-4433a-3p and peroxisome proliferator-activated receptor alpha (PPAR-α) levels in GCs of PCOS patients or in tissues of a PCOS rat model were examined by quantitative polymerase chain reaction and immunohistochemistry. Bioinformatics analyses and luciferase assays were used to examine the association between miR-4433a-3p and PPAR-α, as well as PPAR-α and immune cell infiltration, in PCOS patients. RESULTS: miR-4433a-3p expression in GCs of PCOS patients was increased. miR-4433a-3p overexpression inhibited the growth of the human granulosa-like tumor cell line (KGN) and promoted apoptosis, while co-treatment with PPAR-α and miR-4433a-3p mimic rescued miR-4433a-3p-induced apoptosis. PPAR-α was a direct target of miR-4433a-3p and its expression was decreased in PCOS patients. PPAR-α expression was also positively correlated with the infiltration of activated CD4+ T cells, eosinophils, B cells, gamma delta T cells, macrophages, and mast cells, but negatively correlated with the infiltration of activated CD8+ T cells, CD56+ bright natural killer cells, immature dendritic cells, monocytes, plasmacytoid dendritic cells, neutrophils, and type 1 T helper cells in PCOS patients. CONCLUSION: The miR-4433a-3p/PPAR-α/immune cell infiltration axis may function as a novel cascade to alter GC apoptosis in PCOS.

Hyperuricemia is associated with the progression of IgA nephropathy in children.

BACKGROUND: The objective of the study was to explore the potential biomarkers and risk factors in children with immunoglobulin A nephropathy (IgAN). METHODS: Untargeted metabolomics analysis was performed on children with IgAN before and after treatment. Subsequently, a retrospective study involving the past 15 years and a follow-up study were performed to verify the role of hyperuricemia in IgAN children. RESULTS: Serum metabolomics analyses showed that levels of serum xanthosine were closely related to the outcome of IgAN, and KEGG analyses showed that differential metabolites were significantly enriched in purine metabolism. Furthermore, retrospectively analyses of 252 children with IgAN showed that hyperuricemia was associated with poorer renal outcome. Logistic regression analysis showed that BMI, serum creatinine, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. Kaplan-Meier analysis revealed that kidney progression-free survival in IgAN children with hyperuricemia was lower than that without hyperuricemia, especially in females. CONCLUSIONS: We first performed a dynamic metabolomics study to reveal that hyperuricemia is closely related to the progression of IgAN in children. Then retrospective and follow-up studies confirmed that hyperuricemia is an important risk factor for poor renal outcomes. We need to pay more attention to the hyperuricemia in children with IgAN. IMPACT: We first performed a dynamic metabolomics study to reveal that hyperuricemia was closely related to the progression of IgAN in children. Retrospective analyses in past 15 years confirmed that IgAN children with hyperuricemia had poorer renal function and worse renal pathology. The BMI, Scr, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. The long-term follow-up study showed that hyperuricemia was an important risk factor for poor renal outcome in children with IgAN. We need to pay more attention to hyperuricemia in children with IgAN, especially in females.

Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis.

BACKGROUND: Serum uric acid (SUA) acts as an antioxidant and abnormally low SUA may raise the risk of developing atherosclerotic disorders. There is a U-shaped association between SUA with cardiovascular diseases (CVDs) in general population. However, the prevalence of hypouricemia and its influence on CVDs in rheumatoid arthritis (RA) remains unclear. METHODS: This cross-sectional study collected clinical data from a Chinese RA cohort. Hypouricemia was defined as SUA ≤ 3.0 mg/dL, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL. CVDs were defined as a history of angina pectoris, myocardial infarction, heart failure, stroke and peripheral arterial disease. Restricted cubic spline regression and logistic regression analysis were conducted to evaluate the associations between SUA levels and CVDs. RESULTS: Among 1130 RA patients recruited, the mean age was 53.2 years and 79.0% were female. The prevalence of hypouricemia and hyperuricemia were 10.6% and 12.0%, respectively. RA patients with hyperuricemia had a higher rate of CVDs than normouricemic patients (27.9% vs. 7.1%, P < 0.05). Surprisingly, RA patients with hypouricemia also had a higher rate of CVDs (20.7% vs. 7.1%, P < 0.05) even without higher traditional cardiovascular risk factors. A U-shaped association between SUA levels and total CVDs was found (Pnon-linear < 0.001). Multivariate logistic regression analysis revealed that compared with normouricemia, both hypouricemia [adjusted OR (AOR) = 4.707, 95% CI 2.570-8.620] and hyperuricemia (AOR = 3.707, 95% CI 2.174-6.321) were associated with higher risk of CVDs. CONCLUSIONS: Hypouricemia may be a potential risk factor of CVDs in RA patients.

Myokine myostatin is a novel predictor of one-year radiographic progression in patients with rheumatoid arthritis: A prospective cohort study.

Background: Associations between rheumatoid arthritis (RA) and reduced skeletal muscle have been studied, and we firstly reported myopenia independently predict one-year radiographic progression in RA. Myokine myostatin can negatively regulate skeletal muscle mass and promote osteoclast differentiation. However, there is no report about their relationships in RA patients. We firstly explored the relationship of serum myostatin and disease characteristics, as well as aggravated joint destruction during one-year follow-up. Methods: Consecutive RA patients were recruited from a real-world prospective cohort and completed at least one-year follow-up. Baseline serum level of myostatin was measured by enzyme-linked immunosorbent assay. Clinical data in RA patients as well as muscle index in both RA patients and healthy controls were collected. One-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ≥0.5 units. Results: Totally 344 RA patients (age 47.9 ± 12.5 years, 84.0% female) and 118 healthy control subjects (age 42.8 ± 11.3 years, 74.6% female) were recruited. Compared with healthy controls, RA patients showed a higher level of serum myostatin at baseline (3.241 ± 1.679 ng/ml vs. 1.717 ± 0.872 ng/ml, P<0.001), although lower appendicular skeletal muscle mass index (ASMI, 6.0 ± 0.9 kg/m2 vs. 6.5 ± 1.0 kg/m2, P<0.001). In RA patients, those with high myostatin level showed a higher rate of radiographic progression than low myostatin group (45.3% vs. 18.6%, P<0.001). Furtherly, RA patients were stratified into four subgroups according to serum myostatin and myopenia. Compared with other three subgroups, RA patients with high myostatin overlapping myopenia had the highest rate of radiographic progression (67.2% vs. 10.3%-31.4%, P<0.001), as well as the lowest proportion of remission and the highest rate of physical dysfunction during one-year follow-up. After adjustment for confounding factors, high serum myostatin (AOR=3.451, 95%CI: 2.016-5.905) and myopenia (AOR=2.387, 95%CI: 1.416-4.022) at baseline were risk factors for one-year radiographic progression, especially for those with high myostatin overlapping myopenia (AOR=10.425, 95%CI: 3.959-27.450) as the highest-risk individuals among four subgroups. Significant synergistic interaction effect was observed between high myostatin and myopenia on one-year radiographic progression (AP=66.3%, 95%CI: 43.2%-89.3%). Conclusion: Myostatin is a novel predictor of aggravated joint destruction in RA patients which has synergistic interaction with myopenia for predicting value.

Genome-Wide Analysis of the RNase T2 Family and Identification of Interacting Proteins of Four ClS-RNase Genes in 'XiangShui' Lemon.

S-RNase plays vital roles in the process of self-incompatibility (SI) in Rutaceae plants. Data have shown that the rejection phenomenon during self-pollination is due to the degradation of pollen tube RNA by S-RNase. The cytoskeleton microfilaments of pollen tubes are destroyed, and other components cannot extend downwards from the stigma and, ultimately, cannot reach the ovary to complete fertilisation. In this study, four S-RNase gene sequences were identified from the 'XiangShui' lemon genome and ubiquitome. Sequence analysis revealed that the conserved RNase T2 domains within S-RNases in 'XiangShui' lemon are the same as those within other species. Expression pattern analysis revealed that S3-RNase and S4-RNase are specifically expressed in the pistils, and spatiotemporal expression analysis showed that the S3-RNase expression levels in the stigmas, styles and ovaries were significantly higher after self-pollination than after cross-pollination. Subcellular localisation analysis showed that the S1-RNase, S2-RNase, S3-RNase and S4-RNase were found to be expressed in the nucleus according to laser confocal microscopy. In addition, yeast two-hybrid (Y2H) assays showed that S3-RNase interacted with F-box, Bifunctional fucokinase/fucose pyrophosphorylase (FKGP), aspartic proteinase A1, RRP46, pectinesterase/pectinesterase inhibitor 51 (PME51), phospholipid:diacylglycerol acyltransferase 1 (PDAT1), gibberellin receptor GID1B, GDT1-like protein 4, putative invertase inhibitor, tRNA ligase, PAP15, PAE8, TIM14-2, PGIP1 and p24beta2. Moreover, S3-RNase interacted with TOPP4. Therefore, S3-RNase may play an important role in the SI of 'XiangShui' lemon.

COQ8B glomerular nephropathy: Outcomes after kidney transplantation and analysis of characteristics in Chinese population.

Background: Mutation in the COQ8B gene can cause COQ8B glomerular nephropathy (COQ8B-GN), which is rare and associated with steroid-resistant nephrotic syndrome (SRNS) as well as rapid progression to end-stage renal disease (ESRD). The aim of this study was to analyze the prognosis and recurrence risk of COQ8B-GN in patients after kidney transplantation (KTx) and summarize the characteristics of the Chinese population. Methods: A retrospective study included four cases treated in our hospital with a diagnosis of COQ8B-GN. Chinese and foreign studies were searched from database inception to February 2022. Results: A total of four cases were included, with the age of onset ranging from 4 to 9 years. The initial presentations were SRNS and asymptomatic proteinuria. Only one had an extrarenal manifestation (thyroid cyst). All patients progressed to ESRD at a mean time of 42 months after onset. With a total follow-up time ranging from 12 to 87 months, three of them had received transplantation. While one case needed a second KTx due to graft failure caused by chronic rejection, two recipients had excellent graft function. No recurrence in allograft was observed. There have been 18 cases of KTx recipients reported globally with follow-up information. Except for two cases of graft failure caused by hyperacute rejection and chronic rejection, respectively, the rest all had good graft function without recurrence. In addition, 44 cases of COQ8B-GN in the Chinese population were identified. At the onset, 75% of the patients were aged ≤10 years with initial symptoms of asymptomatic proteinuria, nephrotic syndrome (NS), or SRNS. By the time of literature publication, 59% of patients had progressed to ESRD (mean age of 10.3 ± 3.6 years). The median time from onset to ESRD was 21 months. Renal pathology mainly showed focal segmental glomerulosclerosis (FSGS), accounting for 61.8% of all biopsies, followed by mesangial proliferative glomerulonephritis (20.6%). The first three prevalent mutations in the COQ8B gene among the Chinese population were c. 748G>C, c. 737G>A, and c. 532C>T. Conclusion: COQ8B-GN in the Chinese population may present with asymptomatic proteinuria, NS, or SRNS initially, with most onsets before the age of 10 years. A lot of patients progress to ESRD in early adolescence. FSGS on biopsy and c. 748G>C in the genetic test are the most frequently seen in Chinese COQ8B-GN patients. KTx is feasible for patients with ESRD due to the low risk of recurrence, but we should pay attention to graft rejection.

Sugar-Sweeten Beverage Consumption Is Associated With More Obesity and Higher Serum Uric Acid in Chinese Male Gout Patients With Early Onset.

Background: Early onset gout has received increasing interest from researchers. Previous studies have reported that serum urate (sUA) levels and prevalence of obesity are higher in early onset gout patients than in later-onset gout patients. We explored the dietary habits of early onset and later-onset gout patients and their association with clinical features. Materials and Methods: Gout patients completed a 10-item food frequency questionnaire. Early onset gout patients were defined as gout onset before the age of 40, and onset after age 40 was classified as later-onset. Associations between dietary factors, obesity, and sUA level of ≥600 µmol/L were assessed using logistic regression. Results: Among the 655 gout patients, 94.6% were males, and 59.1% presented with early onset gout. All early onset patients were males. sUA level was significantly higher in the early onset group than in the later-onset group (550.7 vs. 513.4 µmol/L). The proportion of patients with a sUA level of ≥ 600 µmol/L (40.3 vs. 26.2%) and obesity (27.6 vs. 10.7%) was higher in the early onset group than in the later-onset group (all p < 0.05). The early onset group consumed more red meat (101-200 g/day: 43.6 vs. 26.0%), sugar-sweetened beverages (>4 times/week: 27.9 vs. 7.7%), and milk and milk products (1-2 times/week: 28.5 vs. 16.6%), but less alcohol (>84 g/day: 8.5 vs. 21.5%) and tea (>4 times/week: 35.7 vs. 52.4%; all p < 0.05). Sugar-sweetened beverage intake was positively correlated with sUA level of ≥600 µmol/L (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.4, 3.7) and obesity (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.2, 3.7). These correlations remained significant for early onset gout patients. Conclusion: Sugar-sweetened beverage intake replaced alcohol as the main dietary risk factor for gout in early onset patients, and this change was associated with a greater prevalence of obesity and higher sUA level. Clinicians should provide specific dietary education for different generations of gout patients. The epidemic of sugar-sweetened beverage consumption should be considered for the development of public health policies for the prevention of gout.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Cardiovascular Risk in Patients With Rheumatoid Arthritis: A Cross-Sectional Study of Chinese Cohort.

Background: The nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) is considered to identify more cardiovascular disease (CVD) risks in the general population. Patients with rheumatoid arthritis (RA) carry an excess risk for CVD. However, the prevalence of MAFLD and its relationship with CVD risks in RA have not been reported. Methods: This cross-sectional study retrospectively analyzed clinical data from a Chinese RA cohort. MAFLD was diagnosed according to the criteria proposed by an international expert panel from 22 countries in 2020. CVD risk in patients with RA was estimated by the Prediction for Atherosclerotic Cardiovascular Disease Risk in China with a 1.5 multiplication factor. Results: Among 513 included patients with RA, 78.4% were women and the mean ± SD age was 51.8 ± 12.6 years. The prevalence of MAFLD was 21.4%. There were 10.9% patients with RA concomitated with CVD events and 32.4% with a high-estimated 10-year CVD risk. Besides a higher liver fibrosis score and a higher ratio of advanced fibrosis, RA patients with MAFLD had a higher rate of CVD events (17.3 vs. 9.2%) and a higher proportion of high estimated 10-year CVD risk (55.5 vs. 26.1%) than those without. Multivariate logistic regression analysis showed that MAFLD was associated with an increase in CVD events [adjusted odds ratio (AOR) = 2.190, 95% CI 1.135-4.227] and high estimated 10-year CVD risk (AOR = 2.483, 95% CI 1.412-4.365, all p < 0.05). Conclusion: Metabolic dysfunction-associated fatty liver disease was associated with increased CVD risk in patients with RA, which implies the importance of early detection and management of MAFLD in patients with RA.

Preparation and Release of pH-Sensitive ß-Cyclodextrin Derivative Micelles Loaded with Paclitaxel.

In this paper, a new amphiphilic mono-6-ß-cyclodextrin octadecylimine (6-ß-CD-N-ODMA) copolymer was synthesized based on ß-cyclodextrin and octadecylamine, which can self-assemble to form polymeric micelles. Drug-loaded micelles (a new drug carrier) were obtained using 6-ß-CD-N-ODMA and paclitaxel (PTX) by the dialysis method. Orthogonal experiments were used to optimize the preparation method of the drug-loaded micelles. The drug-loading content of the carrier prepared by the optimized method was 1.97%. The physicochemical properties of blank micelles and drug-loaded micelles were evaluated by the fluorescence probe method, infrared spectra, dynamic light scattering, and scanning electron microscopy. The release properties of the carrier were investigated. The carrier has good pH sensitivity and the cumulative release rate after 96 h was 88% in PBS (pH = 5.0). The Ritger-Peppas equation is the optimal model for PTX released at pH 5.0, implying that the hydrolysis effect of 6-ß-CD-N-ODMA is the main reason for PTX release. The results indicate that the developed carrier can increase the solubility of PTX and possess potential for increased clinical efficacy of PTX.

A Matrix Prediction Model for the 6-Month Mortality Risk in Patients With Anti-Melanoma Differentiation-Associated Protein-5-Positive Dermatomyositis.

Objectives: The purpose of this study was to investigate the baseline independent risk factors for predicting 6-month mortality of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM) and develop a matrix prediction model formed by these risk factors. Methods: The hospitalized patients with DM who completed at least 6-month follow-up were recruited as a derivation cohort. The primary exposure was defined as positive anti-MDA5 at the baseline. The primary outcome was all-cause 6-month mortality after enrollment. A matrix prediction model was developed in the derivation cohort, and another published cohort was used for external validation. Results: In derivation cohort, 82 patients with DM were enrolled (mean age of onset 50 ± 11 years and 63% women), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489-17.708), arthritis (OR: 5.184, 95%CI: 1.455-18.467), interstitial lung disease (OR: 7.034, 95%CI: 1.157-42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002-1.017) were the independent associators with positive anti-MDA5 in patients with DM. Patients with anti-MDA5-positive DM had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30 vs. 0%). Among the patients with anti-MDA5-positive DM, compared to the survivors, non-survivors had significantly advanced age of onset (59 ± 6 years vs. 46 ± 9 years), higher rates of fever (75 vs. 18%), positive carcinoma embryonic antigen (CEA, 75 vs. 14%), higher level of ferritin (median 2,858 ug/L vs. 619 ug/L, all p < 0.05). A stepwise multivariate Cox regression showed that ferritin ≥1,250 µg/L (HR: 10.4, 95%CI: 1.8-59.9), fever (HR: 11.2, 95%CI: 2.5-49.9), and positive CEA (HR: 5.2, 95%CI: 1.0-25.7) were the independent risk factors of 6-month mortality. A matrix prediction model was built to stratify patients with anti-MDA5-positive DM into different subgroups with various probabilities of 6-month mortality risk. In an external validation cohort, the observed 6-month all-cause mortality was 78% in high-risk group, 43% in moderate-risk group, and 25% in low-risk group, which shows good accuracy of the model. Conclusion: Baseline characteristics such as fever, ferritin ≥1,250 µg/L, and positive CEA are the independent risk factors for 6-month all-cause mortality in patients with anti-MDA5-positive DM. A novel matrix prediction model composed of these three clinical indicators is first proposed to provide a chance for the exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk.

Lysosomal exocytosis of HSP70 stimulates monocytic BMP6 expression in Sjögren's syndrome.

BMP6 is a central cytokine in the induction of Sjögren's syndrome-associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity.

Application of adrenocorticotropic hormone in recurrent focal segmental glomerulosclerosis post-transplantation: A case report and literature review.

BACKGROUND: The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. METHODS: We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. RESULTS: After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. CONCLUSIONS: ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.

Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at 1 Year in Active Rheumatoid Arthritis.

Objectives: This study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA). Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year. Results: Among 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Conclusions: This novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA.

Motion compensation combining with local low rank regularization for low dose dynamic CT myocardial perfusion reconstruction.

Dynamic CT myocardial perfusion imaging (DCT-MPI) is a reliable examination tool for the assessment of myocardium and vascular, while its special scan protocol may result in excessive radiation exposure to patients and inevitable inter-frame motion. Lowering the tube current is a simple way to reduce radiation exposure. However, low mAs will certainly cause severe image noise, thus may further impact the accuracy of functional hemodynamic parameters, which are used for the assessment of blood supply. In this work, we present a novel scheme applying motion compensation and local low rank regularization (MC-LLR) for obtaining high quality motion compensated DCT-MPI images. Specifically, motion compensation by using robust data decomposition registration (RDDR) was introduced. Robust principal component analysis coupled with optical flow-based registration algorithm were used in RDDR. Then, the local low rank constraint on the motion compensated time series images was applied for the DCT-MPI reconstruction. One healthy mini pig and two patient datasets were used to evaluate the proposed MC-LLR algorithm. Results show that the present method achieved satisfactory image quality with higher CNRs, smaller rRMSEs, and more accurate hemodynamic parameter maps.

Ultrasonography predicts the results of labial salivary gland biopsy in patients with suspected Sjögren's syndrome: a matrix risk model.

OBJECTIVE: Although a positive result of labial salivary gland biopsy (LSGB) is critical for the diagnosis of Sjögren's syndrome, rheumatologists prefer assessing the non-invasive objective items and hope to learn the predicted probability of positive LSGB before referring patients with suspected Sjögren's syndrome to receive biopsy. This study aimed to explore the predictive value of combined B-mode ultrasonography (US) and shear-wave elastography (SWE) examination on LSGB results. METHODS: A derivation cohort and later a validation cohort of patients with suspected Sjögren's syndrome were recruited. All participants received clinical assessments, B-mode US and SWE examination on bilateral parotid and submandibular glands before LSGB. Positive LSGB was defined by a focus score ⩾1 per 4 mm2 of glandular tissue. RESULTS: In the derivation cohort of 91 participants, either the total US scores or the total SWE values of four glands significantly distinguished patients with positive LSGB from those with negative results (area under the curve (AUC) = 0.956, 0.825, both p < 0.001). The positive predictive value (PPV) was 100% in patients with total US scores ⩾9 or with total SWE values ⩾33 kPa. The negative predictive value (NPV) was 100% in patients with total US scores <5, but 68% in patients with total SWE values <27 kPa. A matrix risk model was derived based on the combination of total US scores and total SWE values. Patients can be stratified into high, moderate, and low risk of positive LSGB. In the validation cohort of 52 participants, the PPV was 94% in the high-risk subpopulation and the NPV was 93% in the low-risk subpopulation. CONCLUSION: A novel matrix risk model based on the combined B-mode US and SWE examination can help rheumatologists to make a shared decision with suspected Sjögren's syndrome patients on whether the invasive procedure of LSGB should be performed.