Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations in conjunction with systemic lupus erythematosus: Missed diagnosis or misdiagnosis?

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant systemic microvascular disorder attributed to TREX1 (three-prime repair exonuclease-1) gene mutations, often proned to misdiagnosed. METHODS: We reported a case of RVCL-S coexisting with systemic lupus erythematosus due to a mutation in the TREX1 gene. This study provided a summary and discussion of previously documented cases related to TREX1 mutations or RVCL-S. RESULTS: A 39-year-old female patient visited the clinic due to progressive memory loss and speech difficulties. Magnetic resonance imaging results showed corpus callosum atrophy and multiple subcortical calcifications in both brain hemispheres. Genetic testing revealed a TREX1 gene mutation (c.294dupA). Treatment with immunosuppressive therapy for 2 months led to improvements in communication and mobility. We also summarized previously reported cases providing an overview of TREX1 gene mutation or RCVL-S. CONCLUSION: Our case establishes a compelling foundation for future RVCL-S diagnosis and treatment paradigms. Notably, conducting systemic immunity screening in patients with RVCL-S emerges as a strategic approach to prevent potential diagnostic oversights.

Clinical significance of glomerular IgM deposit in IgA nephropathy: a 5-year follow-up study.

The significance of glomerular IgM deposit intensity in IgA Nephropathy (IgAN) remained ambiguous and requires further research. Patients with biopsy-proven IgAN in our hospital from January 2018 to May 2023 were recruited into this retrospective single-center study. Patients who presented with positive IgM deposit were included in IgM + cohort while patients with negative IgM deposit were included in IgM- cohort. Of the IgM+, patients whose IF intensity of IgM deposits exceeded 1+ formed IgM-H cohort while patients whose IF intensity of IgM deposits was equal to 1+ consisted IgM-L cohort. Pairwise comparisons were performed among these cohorts to determine clinical disparities, following the propensity score matching process. Among 982 IgAN patients, 539 patients presented with positive IgM deposit. The Kaplan-Meier analysis showed that the IgM deposit did not contribute adversely to the outcomes (eGFR decreased from the baseline ≥ 50% continuously or reached end-stage renal disease). However, the Cox regression analysis showed that increased intensity of IgM deposit was an independent risk factor (p = 0.03) in IgM+. The IgM-H exhibited more pronounced segmental glomerulosclerosis (p = 0.02) than the IgM-L, which may also be associated more directly with higher urine protein levels (p = 0.02). Moreover, our generalized linear mixed model demonstrated a remarkably higher urine albumin/creatinine ratio (p < 0.01) and serum creatinine (p = 0.04) levels as well as lower serum albumin (p < 0.01) level in IgM-H persistently during the 5-year follow-up. This study concluded that increased intensity of glomerular IgM deposits may contribute adversely to clinicopathologic presentation and outcome in those IgM + patients.

The efficacy of sacubitril/valsartan in patients receiving peritoneal dialysis with diabetes and heart failure with preserved ejection fraction.

OBJECTIVE: To investigate the efficacy of sacubitril/valsartan in the treatment of peritoneal dialysis (PD) in patients with diabetes and heart failure with preserved ejection fraction (HFpEF). MATERIALS AND METHODS: Patients with diabetes who underwent PD and had HFpEF (n = 64) were divided into two groups: the experimental group (n = 31), which was administered sacubitril/valsartan, and the control group (n = 33), administered valsartan alone. Data were collected before and after treatment to compare the inter-group changes in cardiac function indexes, residual renal function (RRF), and PD adequacy indexes. RESULTS: Compared with the control group, the N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were lower in the experimental group after treatment (Wilcoxon test, p < 0.05). The descent ranges of NT-proBNP, left ventricular end-systolic dimension, and left ventricular fraction shortening, as well as increases in the amplitude of left ventricular ejection fraction after treatment were better in the experimental group than in the control group (t-test, p < 0.05). The descent ranges of residual renal glomerular filtration rate, residual renal Kt/Vurea, and residual renal creatinine clearance, as well as increases in the amplitude of ß2-microglobulin, were lower in the experimental group than in the control group (Wilcoxon test, p < 0.05). However, there were no significant differences between the two groups in the descent ranges of the PD adequacy indexes (Wilcoxon test, p > 0.05). Hyperkalemia occurred in 8 cases (25.81%) in the experimental group and 13 cases (39.39%) in the control group, while hypotension occurred in 2 cases (6.45%) and 1 case (3.03%), respectively. No other adverse effects were observed in either group. CONCLUSION: The findings suggest that sacubitril/valsartan can safely and effectively improve RRF and cardiac function in patients with diabetes combined with HFpEF receiving PD, but it has little effect on PD adequacy.

Early prediction of sepsis-induced respiratory tract infection using a biomarker-based machine-learning algorithm.

Early and differential diagnosis of sepsis is essential to avoid unnecessary antibiotic use and further reduce patient morbidity and mortality. Here, we aimed to identify predictors of sepsis and advance a machine-learning strategy to predict sepsis-induced respiratory tract infection (RTI). Patients with sepsis and RTI were selected via retrospective analysis, and essential population characteristics and laboratory parameters were recorded. To improve the performance of the primary model and avoid over-fitting, a recursive feature elimination with cross-validation (RFECV) strategy was used to screen the optimal subset of biomarkers and construct nine machine-learning models based on this subset; the average accuracy, precision, recall, and F1-score were used for evaluation of the models. We identified 430 patients with sepsis and 686 patients with RTI. A total of 39 features were collected, with 23 features identified for initial model construction. Using the RFECV algorithm, we found that the XGBoost classifier, which only needed to include seven biomarkers, demonstrated the best performance among all prediction models, with an average accuracy of 89.24 ± 2.28, while the Ridge classifier, which included 11 biomarkers, had an average accuracy of only 83.87 ± 4.69. The remaining models had prediction accuracies greater than 88%. We developed nine models for predicting sepsis using a strategy that combined RFECV with machine learning. Among these models, the XGBoost classifier, which included seven biomarkers, showed the best performance and highest accuracy for predicting sepsis and may be a promising tool for the timely identification of sepsis.

Ultraconformable Integrated Wireless Charging Micro-Supercapacitor Skin.

Conformable and wireless charging energy storage devices play important roles in enabling the fast development of wearable, non-contact soft electronics. However, current wireless charging power sources are still restricted by limited flexural angles and fragile connection of components, resulting in the failure expression of performance and constraining their further applications in health monitoring wearables and moveable artificial limbs. Herein, we present an ultracompatible skin-like integrated wireless charging micro-supercapacitor, which building blocks (including electrolyte, electrode and substrate) are all evaporated by liquid precursor. Owing to the infiltration and permeation of the liquid, each part of the integrated device attached firmly with each other, forming a compact and all-in-one configuration. In addition, benefitting from the controllable volume of electrode solution precursor, the electrode thickness is easily regulated varying from 11.7 to 112.5 µm. This prepared thin IWC-MSC skin can fit well with curving human body, and could be wireless charged to store electricity into high capacitive micro-supercapacitors (11.39 F cm-3) of the integrated device. We believe this work will shed light on the construction of skin-attachable electronics and irregular sensing microrobots.

Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice.

Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.

Clearance of lipid droplets by chimeric autophagy-tethering compound ameliorates the age-related macular degeneration phenotype in mice lacking APOE.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the primary impairment of AMD. The earliest clinical hallmark of AMD is drusen, which are yellowish spots mainly composed of lipid droplets (LDs) accumulated under the retinal pigment epithelium (RPE). However, the potential pathogenic role of this excessive LD accumulation in AMD is yet to be determined, partially due to a lack of chemical tools to manipulate LDs specifically. Here, we employed our recently developed Lipid Droplets·AuTophagy Tethering Compounds (LD∙ATTECs) to degrade LDs and to evaluate its consequence on the AMD-like phenotypes in apoe-/- (apolipoprotein E; B6/JGpt-Apoeem1Cd82/Gpt) mouse model. apoe-/- mice fed with high-fat diet (apoe-/--HFD) exhibited excessive LD accumulation in the retina, particularly with AMD-like phenotypes including RPE degeneration, Bruch's membrane (BrM) thickening, drusen-like deposits, and photoreceptor dysfunction. LD·ATTEC treatment significantly cleared LDs in RPE/choroidal tissues without perturbing lipid synthesis-related proteins and rescued RPE degeneration and photoreceptor dysfunction in apoe-/--HFD mice. This observation implied a causal relationship between LD accumulation and AMD-relevant phenotypes. Mechanically, the apoe-/--HFD mice exhibited elevated oxidative stress and inflammatory signals, both of which were mitigated by the LD·ATTEC treatment. Collectively, this study demonstrated that LD accumulation was a trigger for the process of AMD and provided entry points for the treatment of the initial insult of AMD by degrading LDs.Abbreviations: AMD: age-related macular degeneration; APOE: apolipoprotein E; ATTECs: autophagy-tethering compounds; BODIPY: boron-dipyrromethene; BrM: Bruch's membrane; ERG: electroretinogram; HFD: high-fat diet; LD·ATTECs: Lipid Droplets·AuTophagy Tethering Compounds; LDs: lipid droplets; OA: oleic acid; OPL: outer plexiform layer; ROS: reactive oxygen species; RPE: retinal pigment epithelium.

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress.

BACKGROUND: The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS: Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS: Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.

Developing a machine learning prediction algorithm for early differentiation of urosepsis from urinary tract infection.

OBJECTIVES: Early recognition and timely intervention for urosepsis are key to reducing morbidity and mortality. Blood culture has low sensitivity, and a long turnaround time makes meeting the needs of clinical diagnosis difficult. This study aimed to use biomarkers to build a machine learning model for early prediction of urosepsis. METHODS: Through retrospective analysis, we screened 157 patients with urosepsis and 417 patients with urinary tract infection. Laboratory data of the study participants were collected, including data on biomarkers, such as procalcitonin, D-dimer, and C-reactive protein. We split the data into training (80%) and validation datasets (20%) and determined the average model prediction accuracy through cross-validation. RESULTS: In total, 26 variables were initially screened and 18 were statistically significant. The influence of the 18 variables was sorted using three ranking methods to further determine the best combination of variables. The Gini importance ranking method was found to be suitable for variable filtering. The accuracy rates of the six machine learning models in predicting urosepsis were all higher than 80%, and the performance of the artificial neural network (ANN) was the best among all. When the ANN included the eight biomarkers with the highest influence ranking, its model had the best prediction performance, with an accuracy rate of 92.9% and an area under the receiver operating characteristic curve of 0.946. CONCLUSIONS: Urosepsis can be predicted using only the top eight biomarkers determined by the ranking method. This data-driven predictive model will enable clinicians to make quick and accurate diagnoses.

Corrigendum: Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy.

[This corrects the article DOI: 10.3389/fendo.2022.1001349.].

The efficacy and safety of an improved percutaneous peritoneal dialysis catheter placement technique in urgent-start peritoneal dialysis patients: a retrospective cohort study.

BACKGROUND: Urgent-start peritoneal dialysis has high catheterization skill requirements and that early complications. The optimal catheter placement method remains debatable in urgent-start peritoneal dialysis patients. Safe and effective peritoneal dialysis catheterization is needed in clinical work. METHODS: We retrospectively analyzed the data of 34 patients diagnosed with end-stage renal disease who opt for peritoneal dialysis, 19 males and 15 females, with an average age of 62.3±14.7 years, peritoneal dialysis catheter implantation was completed by the improved percutaneous catheterization technique. They were followed for 6 months, early and late complications were observed and the survival rate of the catheter technique was calculated. RESULTS: All 34 patients diagnosed with end-stage renal disease successfully underwent catheter placement using the improved percutaneous technique; the catheterization success rate was 100%. No severe organ injuries, such as intestinal perforation and bladder perforation, occurred intraoperatively. Peritoneal dialysis was started immediately after surgery. The early complications included one case of leakage, one case of omental wrapping, and six cases of rectus abdominis hemorrhage. The late complications included one case of pleuro-abdominal fistula and two cases of peritonitis. The 6-month technical survival rate for the catheter was 94.1% (32/34). Compared to previously reported studies, this technique may reduce leakage and early catheter dysfunction, and improve the technical survival of catheters. CONCLUSIONS: The improved percutaneous peritoneal dialysis catheter placement technique might be an effective and safe method for urgent­start peritoneal dialysis patients.

Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy.

Objective: Thyroid-associated ophthalmopathy (TAO) is a disfiguring autoimmune disease, which destroys the structure of orbital tissues and even threatens vision. Metabolic reprograming is critical in autoimmune diseases; however, the metabolic basis of TAO remains to be clarified. Our study aimed to reveal the metabolic profile of TAO. Methods: Orbital adipose/connective tissues from eleven TAO patients and twelve control subjects were collected during surgeries and analyzed with liquid chromatograph-mass spectrometer. Orthogonal partial least-squares discrimination analysis (OPLS-DA), variable importance in projection (VIP), heat map, and volcano plot were used to reveal metabolic profile in TAO. Pathway analysis and metabolites-gene analysis were utilized to explore potential metabolic metabolism in TAO. Results: 3038 metabolites were detected in samples from the TAO patients and the controls. OPLS-DA analysis of the metabolomics results showed two distinguished groups, demonstrating that TAO has a unique metabolome. Univariate tests identified 593 dysregulated metabolites (P < 0.05), including 367 increased metabolites and 226 decreased metabolites. Pathway analysis showed that changed metabolites were enriched in cholesterol metabolism, choline metabolism in cancer, fat digestion and absorption, regulation of lipolysis in adipocytes, and insulin resistance. In addition, metabolites-gene analysis illustrated that cholesterol metabolism was involved in the pathogenesis of TAO. Endoplasmic reticulum stress-related genes (ATF6, PERK, and IRE1α) expressions were higher in TAO orbital tissues than in control orbital tissues verified by western blot. Additionally, the expression level of diacylglycerol acyltransferase 1 (DGAT1), a key metabolic protein for triacylglycerol synthesis, was increased in orbital tissues of TAO detected by qRT-PCR, indicating disrupted cholesterol metabolism in TAO. Conclusion: The present study demonstrated different metabolite profiles and potential metabolic mechanisms in TAO.

Downregulation of miR-451 in cholangiocarcinoma help the diagnsosi and promotes tumor progression.

BACKGROUND: Cholangiocarcinoma is a kind of invasive malignant tumor followed by hepatocellular carcinoma. miR-451 was suggested to function as regulator in various human tumors, but its role in mediating tumor progression and predicting the prognosis of cholangiocarcinoma remains unknown. The clinical significance and biological function of miR-451 in cholangiocarcinoma were assessed in this study. RESULTS: The tissue and serum expression of miR-451 was decreased in cholangiocarcinoma compared with corresponding normal samples. The downregulation of miR-451 was associated with the progressive TNM stage and positive lymph node metastasis of patients. miR-451 was identified to be an indicator of the diagnosis and prognosis of cholangiocarcinoma distinguishing cholangiocarcinoma patients from healthy volunteers and predicting the poor outcome of patients. miR-451 also served as a tumor suppressor negatively regulating the cellular processes of cholangiocarcinoma. CONCLUSIONS: miR-451 played a vital role in the early detection and risk prediction of cholangiocarcinoma. miR-451 also suppressed the progression of cholangiocarcinoma, which provides a potential therapeutical target for cholangiocarcinoma treatment.

E2F1/CKS2/PTEN signaling axis regulates malignant phenotypes in pediatric retinoblastoma.

Retinoblastoma (RB) is the most common pediatric intraocular malignancy and is a serious vision- and life-threatening disease. The biallelic mutation of the retinoblastoma gene RB1 is the initial event in the malignant transformation of RB, but the exact molecular mechanism is still unclear. E2F transcription factors can be activated by RB1 loss of function and lead to uncontrolled cell division. Among E2F family numbers, E2F1 has higher expression abundance than E2F2 and E2F3 in RB clinical samples. By integrating E2F1 ChIP-seq data, RNA-seq profiling from RB samples and RNA-seq profiling upon E2F1 knockdown, together with pathway analysis, literature searching and experimental validation, we identified Cyclin-dependent kinases regulatory subunit 2 (CKS2) as a novel regulator in regulating tumor-associated phenotypes in RB. CKS2 exhibited aberrantly higher expression in RB. Depletion of CKS2 in Y79 retinoblastoma cell line led to reduced cell proliferation, delayed DNA replication and decreased clonogenic growth. Downregulation of CKS2 also slowed tumor xenograft growth in nude mice. Importantly, reversed expression of CKS2 rescued cancer-associated phenotypes. Mechanistically, transcription factor E2F1 enhanced CKS2 expression through binding to its promoter and CKS2 regulated the cancer-associated PI3K-AKT pathway. This study discovered E2F1/CKS2/PTEN signaling axis regulates malignant phenotypes in pediatric retinoblastoma, and CKS2 may serve as a potential therapeutic target for this disease.

The safety and urate-lowering efficacy of febuxostat in patients undergoing peritoneal dialysis: a retrospective single-arm cohort study of 84 patients.

BACKGROUND: Studies have shown that hyperuricemia (HUA) is an independent risk factor for all-cause death and residual kidney function loss in peritoneal dialysis (PD) patients. The control of blood uric acid (UA) is an important link to improve the prognosis of end-stage renal disease (ESRD). As a therapeutic drug for HUA, febuxostat is rarely studied in PD patients. The purpose of our study is to investigate the safety, efficacy, and effect on residual renal function (RRF) of febuxostat in patients undergoing PD. METHODS: This is a retrospective single-arm cohort study. During the study period which from September 2016 to November 2020, 191 patients underwent PD at this hospital. Among these patients, 84 were administrated for over a period of 3 months and were eventually included. These 84 patients (51 males and 33 females; average age: 55.18 years) were undergoing PD complicated with HUA or gout who received febuxostat during a regular follow-up from January 2018 to November 2020. Serum UA (sUA) levels, blood routine, liver function, and RRF were compared before and after febuxostat administration. Adverse events (AEs) resulting from febuxostat treatment were collected from medical records. RESULTS: All 84 patients were administered febuxostat for over 3 months, including 39 for over 6 months and 26 for over 12 months. Some 60 patients were treated with febuxostat dose of 20 mg/day and the remaining 24 patients received 40 mg/day. Compared with pretreatment level, the mean sUA level was observed to be markedly reduced at 1 month after febuxostat administration (320.2±87.27 vs. 498.8±81.47 µmol/L, P<0.0001) and at 3 months (291.6±82.66 vs. 498.8±81.47 µmol/L, P<0.0001) and subsequently remained at a significantly low level for 12 months. Only 5 patients stopped febuxostat because of its associated AEs. An initial dose of 40 mg/day was associated with a higher rate of AEs compared with dose of 20 mg/day (25% vs. 18.33%, respectively). After febuxostat treatment, no significant differences were observed between RRF in the two groups. CONCLUSIONS: Febuxostat may be safe and efficient in patients undergoing PD and may not impair RRF. Febuxostat administration at dose of 20 mg/day may be an appropriate dose for patients undergoing PD.

Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal viability.

Isocitrate dehydrogenase 3 (IDH3) is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle, which catalyzes the decarboxylation of isocitrate into α-ketoglutarate and concurrently converts NAD+ into NADH. Dysfunction of IDH3B, the ß subunit of IDH3, has been previously correlated with retinal degeneration and male infertility in humans, but tissue-specific effects of IDH3 dysfunction are unclear. Here, we generated Idh3b-KO mice and found that IDH3B is essential for IDH3 activity in multiple tissues. We determined that loss of Idh3b in mice causes substantial accumulation of isocitrate and its precursors in the TCA cycle, particularly in the testes, whereas the levels of the downstream metabolites remain unchanged or slightly increased. However, the Idh3b-KO mice did not fully recapitulate the defects observed in humans. Global deletion of Idh3b only causes male infertility but not retinal degeneration in mice. Our investigation showed that loss of Idh3b causes an energetic deficit and disrupts the biogenesis of acrosome and flagellum, resulting in spermiogenesis arrestment in sperm cells. Together, we demonstrate that IDH3B controls its substrate levels in the TCA cycle, and it is required for sperm mitochondrial metabolism and spermiogenesis, highlighting the importance of the tissue-specific function of the ubiquitous TCA cycle.

Long-term efficacy, safety, and medication compliance of roxadustat on peritoneal dialysis patients with renal anemia affected by the COVID-19 pandemic: a retrospective study.

BACKGROUND: Current studies have limited data on long-term treatment safety and medication compliance of roxadustat for renal anemia in peritoneal dialysis (PD) patients. We aimed to analyze the long-term efficacy, safety, and medication compliance of roxadustat in the treatment of renal anemia in patients with PD who discontinued recombinant human erythropoietin (rhEPO) treatment due to the corona virus disease 2019 (COVID-19) outbreak. METHODS: We retrospectively collected patients who were switched from rhEPO to roxadustat in our hospital due to the pandemic. The criteria for subject inclusion: aged >18 years with a dialysis vintage >3 months, without malignant tumor, no severe cardiovascular and cerebrovascular diseases, and not combined hemodialysis. Patients were followed up until the end of December 2021. Hemoglobin (Hb), red blood cell (RBC) and hematocrit (Hct) were recorded at baseline, month 1-12 and month 20, and iron parameters at baseline, 3, 6, 9, 12, and 20 months were collected. The Morisky Medication Adherence Scale-8 (MMAS-8) was used to score medication compliance during rhEPO treatment and roxadustat treatment, and adverse reactions occurred during treatment were collected. The efficacy and medication compliance of roxadustat were analyzed using Wilcoxon rank sum test or t-test. RESULTS: The median follow-up time was 21.1 (20.6, 21.7) months. After 1 month of treatment, the Hb level was significantly increased by 9.4 g/L (95% CI: 6.0-12.8 g/L) compared with the baseline, follow up at 20 months showed the Hb level had remained stable, increased by 20.7 g/L (95% CI: 15.9-25.4 g/L) compared with before treatment. At the beginning of treatment, total iron binding capacity increased, transferrin saturation and serum ferritin decreased, serum iron remained stable during treatment. During roxadustat treatment, no patient discontinued treatment due to the pandemic, and the Morisky score was improved compared with that during rhEPO treatment [5.75 (4.25, 6.00) vs. 6.75 (5.75, 7.00), P=0.000]. There were no serious adverse events associated with roxadustat were observed. CONCLUSIONS: Roxadustat can effectively improve anemia and had good tolerance in patients undergoing PD who have difficult using rhEPO, and the medication compliance was better than rhEPO during the COVID-19.

Intravenous route to choroidal neovascularization by macrophage-disguised nanocarriers for mTOR modulation.

Retinal pigment epithelial (RPE) is primarily impaired in age-related macular degeneration (AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization (CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor, rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages (termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.

The RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response.

CCCH zinc finger proteins resolve immune responses by degrading the mRNAs of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Here we report that one such family member, monocyte chemotactic protein-induced protein 3 (MCPIP3, also named ZC3H12C or Regnase-3), promotes skin inflammation by simultaneously enhancing TNF in macrophages and repressing IL-6 in plasmacytoid dendritic cells (pDCs). MCPIP3 is positively associated with psoriasis pathogenesis, and highly expressed by macrophages and pDCs. MCPIP3-deficient macrophages produce less TNF and IL-12p40. However, MCPIP3-deficient pDCs secrete significantly more IL-6. This enhanced intradermal IL-6 may alleviate imiquimod-induced skin inflammation. As a result, MCPIP3-deficient mice are protected from imiquimod-induced psoriasiform lesions. Furthermore, early exposure to pDC-derived IL-6 suppresses macrophage-derived TNF and IL-12p40. Mechanistically, MCPIP3 could directly degrade mRNAs of IL-6, Regnase-1, and IκBζ. In turn, Regnase-1 could degrade MCPIP3 mRNAs. Our study identifies a critical post-transcriptional mechanism that synchronizes myeloid cytokine secretion to initiate autoimmune skin inflammation.

Four Biomarkers-Based Artificial Neural Network Model for Accurate Early Prediction of Bacteremia with Low-level Procalcitonin.

OBJECTIVE: Procalcitonin levels above 2.0 ng/mL are associated with a higher risk of severe sepsis. Bacteremia with procalcitonin levels lower than 2.0 ng/mL has not received much attention, and relevant prediction models are lacking. Herein, a panel of biomarkers was used to establish an early predictive model for bacteremia using machine learning approaches. METHODS: Retrospective evaluation of 487 non-bacteremia controls and 444 bacteremia patients with low-level procalcitonin was performed. Clinical data, including procalcitonin, interleukin-6, C-reactive protein, D-dimer, and lactic acid levels, as well as leukocyte, neutrophil, and platelet counts, were used to identify a panel of relevant variables to build a machine learning model. RESULTS: By comparing six prediction models, the performance of an artificial neural network (ANN) was found to be superior to that of other designed models, with a sensitivity of 0.82, a specificity of 0.85, and an accuracy rate of 83.5%. Furthermore, interleukin-6, procalcitonin, D-dimer, and lactic acid were found to be the most influential biomarkers with the potential to predict bacteremia. CONCLUSION: The ANN model described herein holds outstanding predictive performance, with the potential to provide real-time, data-driven predictions of bacteremia.