Diagnostic performance of deep learning in infectious keratitis: a systematic review and meta-analysis protocol.

INTRODUCTION: Infectious keratitis (IK) represents the fifth-leading cause of blindness worldwide. A delay in diagnosis is often a major factor in progression to irreversible visual impairment and/or blindness from IK. The diagnostic challenge is further compounded by low microbiological culture yield, long turnaround time, poorly differentiated clinical features and polymicrobial infections. In recent years, deep learning (DL), a subfield of artificial intelligence, has rapidly emerged as a promising tool in assisting automated medical diagnosis, clinical triage and decision-making, and improving workflow efficiency in healthcare services. Recent studies have demonstrated the potential of using DL in assisting the diagnosis of IK, though the accuracy remains to be elucidated. This systematic review and meta-analysis aims to critically examine and compare the performance of various DL models with clinical experts and/or microbiological results (the current 'gold standard') in diagnosing IK, with an aim to inform practice on the clinical applicability and deployment of DL-assisted diagnostic models. METHODS AND ANALYSIS: This review will consider studies that included application of any DL models to diagnose patients with suspected IK, encompassing bacterial, fungal, protozoal and/or viral origins. We will search various electronic databases, including EMBASE and MEDLINE, and trial registries. There will be no restriction to the language and publication date. Two independent reviewers will assess the titles, abstracts and full-text articles. Extracted data will include details of each primary studies, including title, year of publication, authors, types of DL models used, populations, sample size, decision threshold and diagnostic performance. We will perform meta-analyses for the included primary studies when there are sufficient similarities in outcome reporting. ETHICS AND DISSEMINATION: No ethical approval is required for this systematic review. We plan to disseminate our findings via presentation/publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022348596.

Symptom burden survey and symptom clusters in patients with cervical cancer: a cross-sectional survey.

PURPOSE: The purpose of this study is to determine the incidence and severity of symptoms of patients with cervical cancer within 6 months after radiotherapy and chemotherapy, form a symptom burden report, evaluate the distribution characteristics of symptoms, identify symptom clusters, and provide a basis for clinical doctors and nurses to improve the symptom management of patients with cervical cancer after radiotherapy and chemotherapy. METHODS: The patients with cervical cancer within 6 months after radiotherapy and chemotherapy were recruited to investigate their symptom burden. Exploratory factor analysis was used to identify symptom clusters. RESULTS: A total of 250 patients participated in the study. The study found that the most common symptom among the 40 symptoms was fatigue, and the most serious symptom was nocturia. Based on the occurrence rate and severity of symptoms, nine symptom clusters were identified, including psycho-emotion-related symptom cluster, pain-disturbed sleep-related symptom cluster, menopausal symptom cluster, tinnitus-dizziness-related symptom cluster, urinary-related symptom cluster, dry mouth-bitter taste-related symptom cluster, intestinal-related symptom cluster, memory loss-numbness-related symptom cluster, and emaciation-related symptom cluster. The three most serious symptom clusters are pain-disturbed sleep-related symptom cluster, urinary-related symptom cluster, and memory loss-numbness-related symptom cluster. CONCLUSION: The symptoms of patients with cervical cancer within 6 months after radiotherapy and chemotherapy are complex, and nine symptom clusters can be identified according to the incidence and severity of symptoms. We can find the potential biological mechanism of each symptom cluster through the discussion of previous mechanism research and clinical research. The number of symptom clusters and the number of symptoms within the symptom cluster are closely related to the symptom evaluation scale selected for the study. Therefore, the symptom cluster study urgently needs a targeted symptom evaluation scale that can comprehensively reflect the patient's condition.

Corrigendum to 'Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice' [J. Orthop. Transl.] 38 (2023) 241-255].

[This corrects the article DOI: 10.1016/j.jot.2022.10.015.].

Biomimetic Porous Magnesium Alloy Scaffolds Promote the Repair of Osteoporotic Bone Defects in Rats through Activating the Wnt/ß-Catenin Signaling Pathway.

In this study, biomimetic porous magnesium alloy scaffolds were prepared to repair femoral bone defects in ovariectomized osteoporotic rats. The purpose of the study was to investigate the effect of biomimetic porous magnesium alloy scaffolds on repairing osteoporotic bone defects and possible mechanisms. The animal model of osteoporosis was established in female SD rats. Three months later, a bone defect of 3 mm in diameter and 3 mm in depth was created in the lateral condyle of the right femur. The rats were then randomly divided into two groups: an experimental group and a control group. Four weeks after surgery, gross specimens were observed and micro-CT scans were performed. The repair of osteoporotic femoral defects in rats was studied histologically using HE staining, Masson staining, and Goldner staining. The expression of Wnt5a, ß-catenin, and BMP-2 was measured between groups by immunohistochemical staining. The bone defect was repaired better after the application of biomimetic porous magnesium alloy scaffolds. Immunohistochemical results showed significantly higher expression of Wnt5a, ß-catenin, and BMP-2. To conclude, the biomimetic porous magnesium alloy scaffolds proposed in this paper might promote the repair of osteoporotic femoral bone defects in rats possibly through activating the Wnt/ß-catenin signaling pathway.

pH-sensitive charge-conversion cinnamaldehyde polymeric prodrug micelles for effective targeted chemotherapy of osteosarcoma in vitro.

Introduction: Chemotherapy is a common strategy for the treatment of osteosarcoma. However, its therapeutic efficacy is not ideal due to the low targeting, lowbioavailability, and high toxicity of chemotherapy drugs. Nanoparticles can improve the residence time of drugs at tumor sites through targeted delivery. This new technology can reduce the risk to patients and improve survival rates. To achieve this goal, we developed a pHsensitive charge-conversion polymeric micelle [mPEG-b-P(C7-co-CA) micelles] for osteosarcoma-targeted delivery of cinnamaldehyde (CA). Methods: First, an amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was synthesized through Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization and post-modification, and self-assembled into mPEG-b-P(C7-co-CA) micelles in an aqueous solution. The physical properties of mPEG-b-P(C7-co-CA) micelles, such as critical micelle concentration (CMC), size, appearance, and Zeta potential were characterized. The CA release curve of mPEG-b-P(C7-co-CA) micelles at pH 7.4, 6.5 and 4.0 was studied by dialysis method, then the targeting ability of mPEG-b-P(C7-co-CA) micelles to osteosarcoma 143B cells in acidic environment (pH 6.5) was explored by cellular uptakeassay. The antitumor effect of mPEG-b-P(C7-co-CA) micelles on 143B cells in vitro was studied by MTT method, and the level of reactive oxygen species (ROS) in 143B cells after mPEG-b-P(C7-co-CA) micelles treatment was detected. Finally, the effects of mPEG-b-P(C7-co-CA) micelles on the apoptosis of 143B cells were detected by flow cytometry and TUNEL assay. Results: An amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was successfully synthesized and self-assembled into spheric micelles with a diameter of 227 nm. The CMC value of mPEG-b-P(C7-co-CA) micelles was 25.2 mg/L, and it showed a pH dependent release behavior of CA. mPEG-b-P(C7-co-CA) micelles can achieve chargeconversion from a neutral to a positive charge with decreasing pHs. This charge-conversion property allows mPEG-b-P(C7-co-CA) micelles to achieve 143B cell targeting at pH 6.5. In addition, mPEG-b-P(C7-co-CA) micelles present high antitumor efficacy and intracellular ROS generation at pH 6.5 which can induce 143B cell apoptosis. Discussion: mPEG-b-P(C7-co-CA) micelles can achieve osteosarcoma targeting effectively and enhance the anti-osteosarcoma effect of cinnamaldehyde in vitro. This research provides a promising drug delivery system for clinical application and tumor treatment.

"Cross-talk" between gut microbiome dysbiosis and osteoarthritis progression: a systematic review.

Objectives: The aim of this systematic review was to summarize the available literature on gut microbiome (GMB) and osteoarthritis (OA), analyze the correlation between GMB and OA, and explore potential underlying mechanisms. Methods: A systematic search of the PubMed, Embase, Cochrane, and Web of Science with the keywords "Gut Microbiome" and "Osteoarthritis" was conducted to identify the human and animal studies exploring the association between GMB and OA. The retrieval time range was from the database inception to July 31, 2022. Studies reported the other arthritic diseases without OA, reviews, and studies focused on the microbiome in other parts of the body with OA, such as oral or skin, were excluded. The included studies were mainly reviewed for GMB composition, OA severity, inflammatory factors, and intestinal permeability. Results: There were 31 studies published met the inclusion criteria and were analyzed, including 10 human studies and 21 animal studies. Human and animal studies have reached a consistent conclusion that GMB dysbiosis could aggravate OA. In addition, several studies have found that alterations of GMB composition can increase intestinal permeability and serum levels of inflammatory factors, while regulating GMB can alleviate the changes. Owing to the susceptibility of GMB to internal and external environments, genetics, and geography, the included studies were not consistent in GMB composition analysis. Conclusion: There is a lack of high-quality studies evaluating the effects of GMB on OA. Available evidence indicated that GMB dysbiosis aggravated OA through activating the immune response and subsequent induction of inflammation. Future studies should focus on more prospective, cohort studies combined with multi-omics to further clarify the correlation.

The Thioredoxin System in Edwardsiella piscicida Contributes to Oxidative Stress Tolerance, Motility, and Virulence.

Edwardsiella piscicida is an important fish pathogen that causes substantial economic losses. In order to understand its pathogenic mechanism, additional new virulence factors need to be identified. The bacterial thioredoxin system is a major disulfide reductase system, but its function is largely unknown in E. piscicida. In this study, we investigated the roles of the thioredoxin system in E. piscicida (named TrxBEp, TrxAEp, and TrxCEp, respectively) by constructing a correspondingly markerless in-frame mutant strain: ΔtrxB, ΔtrxA, and ΔtrxC, respectively. We found that (i) TrxBEp is confirmed as an intracellular protein, which is different from the prediction made by the Protter illustration; (ii) compared to the wild-type strain, ΔtrxB exhibits resistance against H2O2 stress but high sensitivity to thiol-specific diamide stress, while ΔtrxA and ΔtrxC are moderately sensitive to both H2O2 and diamide conditions; (iii) the deletions of trxBEp, trxAEp, and trxCEp damage E. piscicida's flagella formation and motility, and trxBEp plays a decisive role; (iv) deletions of trxBEp, trxAEp, and trxCEp substantially abate bacterial resistance against host serum, especially trxBEp deletion; (v) trxAEp and trxCEp, but not trxBEp, are involved in bacterial survival and replication in phagocytes; (vi) the thioredoxin system participates in bacterial dissemination in host immune tissues. These findings indicate that the thioredoxin system of E. piscicida plays an important role in stress resistance and virulence, which provides insight into the pathogenic mechanism of E. piscicida.

TFOS Lifestyle: Impact of cosmetics on the ocular surface.

In this report the use of eye cosmetic products and procedures and how this represents a lifestyle challenge that may exacerbate or promote the development of ocular surface and adnexal disease is discussed. Multiple aspects of eye cosmetics are addressed, including their history and market value, psychological and social impacts, possible problems associated with cosmetic ingredients, products, and procedures, and regulations for eye cosmetic use. In addition, a systematic review that critically appraises randomized controlled trial evidence concerning the ocular effects of eyelash growth products is included. The findings of this systematic review highlight the evidence gaps and indicate future directions for research to focus on ocular surface outcomes associated with eyelash growth products.

TFOS Lifestyle - Evidence quality report: Advancing the evaluation and synthesis of research evidence.

Evidence-based practice is a dominant paradigm in healthcare that emphasizes the importance of ensuring the translation of the best available, relevant research evidence into practice. An Evidence Quality Subcommittee was established to provide specialized methodological support and expertise to promote rigorous and evidence-based approaches for the Tear Film and Ocular Surface Society (TFOS) Lifestyle Epidemic reports. The present report describes the purpose, scope, and activity of the Evidence Quality Subcommittee in the undertaking of high-quality narrative-style literature reviews, and leading prospectively registered, reliable systematic reviews of high priority research questions, using standardized methods for each topic area report. Identification of predominantly low or very low certainty evidence across the eight systematic reviews highlights a need for further research to define the efficacy and/or safety of specific lifestyle interventions on the ocular surface, and to clarify relationships between certain lifestyle factors and ocular surface disease. To support the citation of reliable systematic review evidence in the narrative review sections of each report, the Evidence Quality Subcommittee curated topic-specific systematic review databases and relevant systematic reviews underwent standardized reliability assessment. Inconsistent methodological rigor was noted in the published systematic review literature, emphasizing the importance of internal validity assessment. Based on the experience of implementing the Evidence Quality Subcommittee, this report makes suggestions for incorporation of such initiatives in future international taskforces and working groups. Content areas broadly relevant to the activity of the Evidence Quality Subcommittee, including the critical appraisal of research, clinical evidence hierarchies (levels of evidence), and risk of bias assessment, are also outlined.

Rapid Prediction of Multidrug-Resistant Klebsiella pneumoniae through Deep Learning Analysis of SERS Spectra.

Klebsiella pneumoniae is listed by the WHO as a priority pathogen of extreme importance that can cause serious consequences in clinical settings. Due to its increasing multidrug resistance all over the world, K. pneumoniae has the potential to cause extremely difficult-to-treat infections. Therefore, rapid and accurate identification of multidrug-resistant K. pneumoniae in clinical diagnosis is important for its prevention and infection control. However, the limitations of conventional and molecular methods significantly hindered the timely diagnosis of the pathogen. As a label-free, noninvasive, and low-cost method, surface-enhanced Raman scattering (SERS) spectroscopy has been extensively studied for its application potentials in the diagnosis of microbial pathogens. In this study, we isolated and cultured 121 K. pneumoniae strains from clinical samples with different drug resistance profiles, which included polymyxin-resistant K. pneumoniae (PRKP; n = 21), carbapenem-resistant K. pneumoniae, (CRKP; n = 50), and carbapenem-sensitive K. pneumoniae (CSKP; n = 50). For each strain, a total of 64 SERS spectra were generated for the enhancement of data reproducibility, which were then computationally analyzed via the convolutional neural network (CNN). According to the results, the deep learning model CNN plus attention mechanism could achieve a prediction accuracy as high as 99.46%, with robustness score of 5-fold cross-validation at 98.87%. Taken together, our results confirmed the accuracy and robustness of SERS spectroscopy in the prediction of drug resistance of K. pneumoniae strains with the assistance of deep learning algorithms, which successfully discriminated and predicted PRKP, CRKP, and CSKP strains. IMPORTANCE This study focuses on the simultaneous discrimination and prediction of Klebsiella pneumoniae strains with carbapenem-sensitive, carbapenem-resistant, and polymyxin-resistant phenotypes. The implementation of CNN plus an attention mechanism makes the highest prediction accuracy at 99.46%, which confirms the diagnostic potential of the combination of SERS spectroscopy with the deep learning algorithm for antibacterial susceptibility testing in clinical settings.

Antibiotics versus placebo for acute bacterial conjunctivitis.

BACKGROUND: Acute bacterial conjunctivitis is an infection of the conjunctiva and is one of the most common ocular disorders in primary care. Antibiotics are generally prescribed on the basis that they may speed recovery, reduce persistence, and prevent keratitis. However, many cases of acute bacterial conjunctivitis are self-limited, resolving without antibiotic therapy. This Cochrane Review was first published in The Cochrane Library in 1999, then updated in 2006, 2012, and 2022. OBJECTIVES: To assess the benefits and side effects of antibiotic therapy in the management of acute bacterial conjunctivitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2022, Issue 5), MEDLINE (January 1950 to May 2022), Embase (January 1980 to May 2022), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www. CLINICALTRIALS: gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases in May 2022.   SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which any form of antibiotic treatment, with or without steroid, had been compared with placebo/vehicle in the management of acute bacterial conjunctivitis. This included topical and systemic antibiotic treatments. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles and abstracts of identified studies. We assessed the full text of all potentially relevant studies and determined the included RCTs, which were further assessed for risk of bias using Cochrane methodology. We performed data extraction in a standardized manner and conducted random-effects meta-analyses using RevMan Web. MAIN RESULTS: We included 21 eligible RCTs, 10 of which were newly identified in this update. A total of 8805 participants were randomized. All treatments were topical in the form of drops or ointment. The trials were heterogeneous in terms of their eligibility criteria, the nature of the intervention (antibiotic drug class, which included fluoroquinolones [FQs] and non-FQs; dosage frequency; duration of treatment), the outcomes assessed and the time points of assessment. We judged one trial to be of high risk of bias, four as low risk of bias, and the others as raising some concerns. Based on intention-to-treat (ITT) population, antibiotics likely improved clinical cure (resolution of clinical symptoms or signs) by 26% (RR 1.26, 95% CI 1.09 to 1.46; 5 trials, 1474 participants; moderate certainty) as compared with placebo. Subgroup analysis showed no differences by antibiotic class (P = 0.67) or treatment duration (P = 0.60). In the placebo group, 55.5% (408/735) of participants had spontaneous clinical resolution by days 4 to 9 versus 68.2% (504/739) of participants treated with an antibiotic. Based on modified ITT population, in which participants were analyzed after randomization on the basis of positive microbiological culture, antibiotics likely increased microbiological cure (RR 1.53, 95% CI 1.34 to 1.74; 10 trials, 2827 participants) compared with placebo at the end of therapy; there were no subgroup differences by drug class (P = 0.60). No study evaluated the cost-effectiveness of antibiotic treatment. Patients receiving antibiotics had a lower risk of treatment incompletion than those in the placebo group (RR 0.64, 95% CI 0.52 to 0.78; 13 trials, 5573 participants; moderate certainty) and were 27% less likely to have persistent clinical infection (RR 0.73, 95% CI 0.65 to 0.81; 19 trials, 5280 participants; moderate certainty). There was no evidence of serious systemic side effects reported in either the antibiotic or placebo group (very low certainty). When compared with placebo, FQs (RR 0.70, 95% CI 0.54 to 0.90) but not non-FQs (RR 4.05, 95% CI 1.36 to 12.00) may result in fewer participants with ocular side effects. However, the estimated effects were of very low certainty. AUTHORS' CONCLUSIONS: The findings of this update suggest that the use of topical antibiotics is associated with a modestly improved chance of resolution in comparison to the use of placebo. Since no evidence of serious side effects was reported, use of antibiotics may therefore be considered to achieve better clinical and microbiologic efficacy than placebo. Increasing the proportion of participants with clinical cure or increasing the speed of recovery or both are important for individual return to work or school, allowing people to regain quality of life. Future studies may examine antiseptic treatments with topical antibiotics for reasons of cost and growing antibiotic resistance.

Rac1/PAK1 signaling contributes to bone cancer pain by Regulation dendritic spine remodeling in rats.

Bone cancer pain (BCP) is severe chronic pain caused by tumor metastasis to the bones, often resulting in significant skeletal remodeling and fractures. Currently, there is no curative treatment. Therefore, insight into the underlying mechanisms could guide the development of mechanism-based therapeutic strategies for BCP. We speculated that Rac1/PAK1 signaling plays a critical role in the development of BCP. Tumor cells implantation (TCI) into the tibial cavity resulted in bone cancer-associated mechanical allodynia. Golgi staining revealed changes in the excitatory synaptic structure of WDR (Wide-dynamic range) neurons in the spinal cord, including increased postsynaptic density (PSD) length and thickness, and width of the cleft. Behavioral and western blotting test revealed that the development and persistence of pain correlated with Rac1/PAK1 signaling activation in primary sensory neurons. Intrathecal injection of NSC23766, a Rac1 inhibitor, reduced the persistence of BCP as well as reversed the remodeling of dendrites. Therefore, we concluded that activation of the Rac1/PAK1 signaling pathway in the spinal cord plays an important role in the development of BCP through remodeling of dendritic spines. Modulation of the Rac1/PAK1 pathway may be a potential strategy for BCP treatment.

Prognostic Significance of Ribosome-related Genes Signature in Diffuse Large B Cell Lymphoma.

Background: The diffuse large B-cell lymphoma (DLBCL) is a heterogeneous lymphoma with a dismal outcome, due to approximately 40% patients will be relapsed or refractory to the standard therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Therefore, we need urgently to explore the approach to classify the risk of DLBCL patients accurately and accurately targeting therapy. The ribosome is a vital cellular organelle that is mainly responsible for translation mRNA into protein, moreover, more and more reports revealed that ribosome was associated with cellular proliferation and tumorigenesis. Therefore, our study aimed to construct a prognostic model of DLBCL patients using ribosome-related genes (RibGs). Method: We screened differentially expressed RibGs between healthy donors' B cells and DLBCL patients' malignant B cells in GSE56315 dataset. Next, we performed analyses of univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses to establish the prognostic model consisting of 15 RibGs in GSE10846 training set. Then, we validated the model by a range of analyses including Cox regression, Kaplan-Meier survival, ROC curve, and nomogram in training and validation cohorts. Results: The RibGs model showed a reliably predictive capability. We found the upregulated pathways in high-risk group most associated with innate immune reaction such as interferon response, complement and inflammatory responses. In addition, a nomogram including age, gender, IPI score and risk score was constructed to help explain the prognostic model. We also discovered the high-risk patients were more sensitive to some certain drugs. Finally, knocking out the NLE1 could inhibit the proliferation of DLBCL cell lines. Conclusion: As far as we know, it is the first time to predict the prognosis of DLBCL using the RibGs and give a new sight for DLBCL treatment. Importantly, the RibGs model could be acted as a supplementary to the IPI in classifying the risk of DLBCL patients.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets.

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.

IgG4-related kidney disease complicated with retroperitoneal fibrosis: A case report.

BACKGROUND: IgG4-related disease (IgG4-RD) is a chronic fibrotic disease mediated by immunity recognized by clinicians in recent years. When the kidney is involved, it is called IgG4-related kidney disease (IgG4-RKD). IgG4-related tubulointerstitial nephritis (IgG4-TIN) is a representative manifestation of IgG4-RKD. IgG4-TIN can cause obstructive nephropathy complicated by retroperitoneal fibrosis (RPF). Cases of IgG4-TIN complicated with RPF are rare. Glucocorticoids are the first-line therapeutic medication for IgG4-RD and can significantly improve renal function. CASE SUMMARY: Herein, we report the case of a 56-year-old man with IgG4-RKD complicated with RPF. The patient presented to the hospital with complaints of elevated serum creatinine (Cr), nausea, and vomiting. During hospitalization, Cr was 1448.6 µmol/L, and serum IgG4 was increased. A total abdominal computed tomography (CT) scan and enhanced CT scan obviously indicated RPF. Although this patient had a long course and renal insufficiency, we performed a kidney biopsy. Renal biopsy showed that the renal tubulointerstitium had focal plasma cell infiltration and increased lymphocyte infiltration accompanied by fibrosis. After combining the biopsy results with immunohistochemistry, it was found that the absolute number of positive IgG4+ cells per high power field exceeded 10, and the ratio of IgG4/IgG was over 40%. Finally, the patient was diagnosed with IgG4-TIN complicated with RPF and given glucocorticoids as long-term maintenance therapy, helping him keep out of dialysis. After a follow-up of 19 mo, the patient had recovered well. Previous literature on IgG4-RKD and RPF was retrieved from PubMed to characterize the clinical and pathological features and to identify the diagnosis and treatment of IgG4-RKD. CONCLUSION: Our case report demonstrates the clinical characteristics of IgG4-RKD complicated with RPF. Serum IgG4 is a favorable indicator for screening. Performing renal biopsy actively plays a vital role in diagnosis and treatment, even if the patient has a long course and manifests with renal insufficiency. It is remarkable to treat IgG4-RKD with glucocorticoids. Hence, early diagnosis and targeted therapy are essential for reversing renal function and improving extrarenal manifestations in patients with IgG4-RKD.

Atomic Insight into the Successive Antiferroelectric-Ferroelectric Phase Transition in Antiferroelectric Oxides.

Antiferroelectrics characterized by voltage-driven reversible transitions between antiparallel and parallel polarity are promising for cutting-edge electronic and electrical power applications. Wide-ranging explorations revealing the macroscopic performances and microstructural characteristics of typical antiferroelectric systems have been conducted. However, the underlying mechanism has not yet been fully unraveled, which depends largely on the atomistic processes. Herein, based on atomic-resolution transmission electron microscopy, the deterministic phase transition pathway along with the underlying lattice-by-lattice details in lead zirconate thin films was elucidated. Specifically, we identified a new type of ferrielectric-like dipole configuration with both angular and amplitude modulations, which plays the role of a precursor for a subsequent antiferroelectric to ferroelectric transformation. With the participation of the ferrielectric-like phase, the phase transition pathways driven by the phase boundary have been revealed. We provide new insights into the consecutive phase transformation in low-dimensional lead zirconate, which thus would promote potential antiferroelectric-based multifunctional devices.

Circular RNA METTL9 contributes to neuroinflammation following traumatic brain injury by complexing with astrocytic SND1.

BACKGROUND: Circular RNAs (circRNAs) are highly enriched in the central nervous system and have been implicated in neurodegenerative diseases. However, whether and how circRNAs contribute to the pathological processes induced by traumatic brain injury (TBI) has not been fully elucidated. METHODS: We conducted a high-throughput RNA sequencing screen for well-conserved, differentially expressed circRNAs in the cortex of rats subjected to experimental TBI. Circular RNA METTL9 (circMETTL9) was ultimately identified as upregulated post-TBI and further characterized by RT-PCR and agarose gel electrophoresis, Sanger sequencing, and RNase R treatment. To examine potential involvement of circMETTL9 in neurodegeneration and loss of function following TBI, circMETTL9 expression in cortex was knocked-down by microinjection of a shcircMETTL9 adeno-associated virus. Neurological functions were evaluated in control, TBI, and TBI-KD rats using a modified neurological severity score, cognitive function using the Morris water maze test, and nerve cell apoptosis rate by TUNEL staining. Pull-down assays and mass spectrometry were conducted to identify circMETTL9-binding proteins. Co-localization of circMETTL9 and SND1 in astrocytes was examined by fluorescence in situ hybridization and immunofluorescence double staining. Changes in the expression levels of chemokines and SND1 were estimated by quantitative PCR and western blotting. RESULTS: CircMETTL9 was significantly upregulated and peaked at 7 d in the cerebral cortex of TBI model rats, and it was abundantly expressed in astrocytes. We found that circMETTL9 knockdown significantly attenuated neurological dysfunction, cognitive impairment, and nerve cell apoptosis induced by TBI. CircMETTL9 directly bound to and increased the expression of SND1 in astrocytes, leading to the upregulation of CCL2, CXCL1, CCL3, CXCL3, and CXCL10, and ultimately to enhanced neuroinflammation. CONCLUSION: Altogether, we are the first to propose that circMETTL9 is a master regulator of neuroinflammation following TBI, and thus a major contributor to neurodegeneration and neurological dysfunction.