bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Acquired Haemophilia A Following mRNA-1273 Booster Vaccination Against SARS-CoV-2 With Concurrent Diagnosis of Pleomorphic Dermal Sarcoma
Authors: Plüß Marlene , Mitteldorf Christina , Szuszies Christoph Johannes , Tampe Björn
Published: April 2022

While the global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is still ongoing and new virus variants are emerging, there is a universal need for vaccines to protect individuals from severe complications and ideally control the pandemic by enabling herd immunity. Several vaccines against SARS-CoV-2 have been approved and are widely used to stem the recurring waves of coronavirus disease 2019 (COVID-19). Post-marketing surveillance is essential to record even rare safety issues related to these new vaccines. Among these issues, several autoimmune phenomena have been recorded in temporal association with and feasibly triggered by a vaccination. Acquired haemophilia A (AHA) is a rare condition characterized by new-onset haemorrhagic diathesis caused by an inhibitor of blood clotting factor VIII (FVIII), often in the elderly and most commonly associated with autoimmune or malignant disease. There have been a small number of AHA cases triggered by vaccinations, including those against SARS-CoV-2. We report the first case of AHA in temporal association with an mRNA-1273 booster vaccination. The diagnosis was made promptly, and the patient received appropriate care including immunosuppression using glucocorticoids, cyclophosphamide (CYC) and rituximab (RTX). The haemorrhage ceased after escalation of treatment, and the patient is recovering. Concurrent malignancy was initially ruled out using a wide scope of diagnostic tests, but pleomorphic dermal sarcoma (PDS) of the forehead occurred after initiation of specific AHA immunosuppressive treatment. Since large vaccination programs are ongoing worldwide and potential adverse events during post-marketing surveillance have been reported following vaccination against SARS-CoV-2, this case illustrates challenges in rare events occurring in association with SARS-CoV-2 vaccination and to proof a causal relationship. Therefore, there is an urgent need for reporting any events in association with SARS-CoV-2 vaccination, but also a crucial discussion about possible concurrent triggers and follow-up information about individual patients.
Identification of Molecular Correlations Between DHRS4 and Progressive Neurodegeneration in Amyotrophic Lateral Sclerosis By Gene Co-Expression Network Analysis
Authors: Li Shu , Zhu Yu , Wei Caihui , Li Cheng , Chen Wenzhi , Jiang Shishi , Yuan Dongxiang , Xu Renshi
Published: April 2022

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and its candidate biomarkers have not yet been fully elucidated in previous studies. Therefore, with the present study, we aim to define and verify effective biomarkers of ALS by bioinformatics. Here, we employed differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), enrichment analysis, immune infiltration analysis, and protein–protein interaction (PPI) to identify biomarkers of ALS. To validate the biomarkers, we isolated the lumbar spinal cord from mice and characterized them using Western blotting and immunofluorescence. The results showed that Dhrs4 expression in the spinal cord was upregulated with the progression of SOD1G93A mice, and the upregulation of DHRS4 and its synergistic DHRS3 might be primarily associated with the activation of the complement cascade in the immune system (C1QA, C1QB, C1QC, C3, and ITGB2), which might be a novel mechanism that induces spinal neurodegeneration in ALS. We propose that DHRS4 and its synergistic DHRS3 are promising molecular markers for detecting ALS progression.
Skin γδ T Cells and Their Function in Wound Healing
Authors: Hu Wengang , Shang Ruoyu , Yang Jiacai , Chen Cheng , Liu Zhihui , Liang Guangping , He Weifeng , Luo Gaoxing
Published: April 2022

For the skin immune system, γδ T cells are important components, which help in defensing against damage and infection of skin. Compared to the conventional αβ T cells, γδ T cells have their own differentiation, development and activation characteristics. In adult mice, dendritic epidermal T cells (DETCs), Vγ4 and Vγ6 γδ T cells are the main subsets of skin, the coordination and interaction among them play a crucial role in wound repair. To get a clear overview of γδ T cells, this review synopsizes their derivation, development, colonization and activation, and focuses their function in acute and chronic wound healing, as well as the underlining mechanism. The aim of this paper is to provide cues for the study of human epidermal γδ T cells and the potential treatment for skin rehabilitation.
Prevalence and Outcome of Serum Autoantibodies in Chronic Hepatitis C Patients Undergoing Direct-Acting Antiviral Treatment
Authors: Romano Ciro , Tortorella Olga , Dalla Mora Liliana , Di Stasio Dario , Sellitto Ausilia , Adinolfi Luigi Elio , Marrone Aldo
Published: April 2022

Background

Chronic immune stimulation by hepatitis C virus (HCV) may cause occurrence of several autoantibodies in infected patients, with or without features of clinically overt autoimmune diseases. The recent introduction of direct-acting antivirals (DAAs) has dramatically changed the natural history of chronic HCV infection. The aim of this study was to assess the effects of DAA therapy on serum autoantibodies in chronic hepatitis C (CHC) patients.

Methods

The medical records of 113 CHC patients were reviewed to assess autoantibody behavior following DAA-directed HCV eradication. Statistical analysis was performed to assess correlations between DAA treatment and autoantibody titers, HCV genotypes, and viral loads.

Results

Anti-nuclear (ANA), anti-smooth muscle cell (ASMA) and anti-mitochondrial (AMA) antibody testing was available in 77 patients; 31 out of 77 patients (40%) had one or more serum autoantibodies prior to treatment. Measurement of autoantibody titers before and after HCV eradication was performed in 20 of 31 patients. DAA treatment significantly affected ANA and ASMA titers, leading to disappearance or reduction of autoantibody titers; conversely, AMA were not influenced by DAA treatment. No correlations were observed between autoantibody specificity and both HCV genotypes and viral loads at baseline. Likewise, serum autoantibody titers were independent of HCV genotypes.

Conclusions

DAA-directed HCV clearance may interrupt chronic immune stimulation by removing the drive for autoantibody induction. The isolated persistence of autoantibodies in the small fraction of patients who did not show clearance following DAA treatment may require long-term vigilance.
Epstein-Barr Virus-Positive Lymphoma-Associated Hemophagocytic Syndrome: A Retrospective, Single-Center Study of 51 Patients
Authors: Zhao Ailin , Yang Jinrong , Li Meng , Li Linfeng , Gan Xinai , Wang Jie , Li He , Shen Kai , Yang Yunfan , Niu Ting
Published: April 2022

Purpose

To investigate clinical characteristics, management, and prognosis of Epstein-Barr virus (EBV)-positive lymphoma-associated hemophagocytic syndrome (LAHS) patients in real-world practice.

Methods

This was a retrospective, single-center cohort study. EBV-positive LAHS patients diagnosed from January 2010 to December 2021 in our center were enrolled. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted.

Results

Of the 51 patients, 44 were T/NK cell lymphoma; five were B cell lymphoma; two were Hodgkin lymphoma. EBV-positive T/NK cell LAHS patients were significantly younger and showed lower fibrinogen levels and C-reactive protein levels than EBV-positive B cell LAHS patients (P=0.033, P=0.000, and P=0.004, respectively). Combined treatment of anti-hemophagocytic lymphohistiocytosis (HLH) and anti-lymphoma treatment was conducted in 24 patients; anti-HLH treatment was conducted in 18 patients; anti-lymphoma treatment was conducted in three patients; glucocorticoid treatment was conducted in one patient. ORR was 47.8%, and the median OS was 61 (95% confidence interval 47.9-74.1) days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed higher ORR and OS than those of anti-HLH patients (P=0.103, and P=0.003, respectively). Elevated alanine aminotransferase level was the independent risk factor of EBV-positive LAHS prognosis.

Conclusions

Prognosis of EBV-positive LAHS patients was poor. Anti-lymphoma treatment should be initiated as soon as HLH was rapidly controlled.
A Cross-Linked Poly(Ethylene Oxide)-Based Electrolyte for All-Solid-State Lithium Metal Batteries With Long Cycling Stability
Authors: Xin Chengzhou , Wen Kaihua , Guan Shundong , Xue Chuanjiao , Wu Xinbin , Li Liangliang , Nan Ce-Wen
Published: April 2022

A cross-linked poly(ethylene oxide) (PEO)-based electrolyte with polyaryl polymethylene isocyanate (PAPI) as the cross-linking agent is synthesized by a facile one-pot reaction. The PEO chains are cross-linked by PAPI through the reaction between hydroxyl groups (−OH) and isocyanate groups (−N=C=O). The effects of PAPI on the electrochemical performance of the PEO-based electrolyte and the stability of the electrolyte/electrode interface are investigated. The PEO–PAPI electrolyte has an ionic conductivity of 9.3 × 10–5−1.3 × 10–4 S cm−1 at 60°C. The cross-linked PEO–PAPI electrolyte exhibits enhanced mechanical properties compared to pristine PEO and shows good compatibility with a lithium (Li) metal anode. An all-solid-state Li metal battery (ASSLMB) with the optimized PEO–PAPI electrolyte and a LiFePO4 cathode (1.62 mg cm−2 in mass loading) shows a discharge capacity of 112.8 mAh g−1 after 700 cycles with a current density of 88 μA cm−2 at 60°C. Even with a high mass loading of 8.4 mg cm−2, the ASSLMB with the cross-linked PEO-based electrolyte shows a good cycle performance. The experimental data show that the cross-linked PEO–PAPI electrolyte is a promising candidate for solid electrolytes used in ASSLMBs.
Influence of IOL Weight on Long-Term IOL Stability in Highly Myopic Eyes
Authors: Chen Yuxi , Meng Jiaqi , Cheng Kaiwen , Lu Qiang , Wei Ling , Lu Yi , Zhu Xiangjia
Published: April 2022

Purpose

This study aimed to investigate the influence of intraocular lens (IOL) weight on long-term IOL stability in highly myopic eyes.

Materials and Methods

A total of 205 highly myopic cataract eyes of 205 patients implanted with the MC X11 ASP (Group A, 86 eyes) or 920H IOL (Group B, 119 eyes) were included in this retrospective study. Eyes were divided into 3 subgroups according to the IOL power: low (≥-5 to <5 D), medium (≥5 to <14 D), and high (≥14 D) IOL power. At 3 years after surgery, IOL decentration and tilt, high-order aberrations, and anterior capsular opening (ACO) area were measured. The influence of IOL weight on long-term IOL stability was evaluated.

Results

Group B had a significantly greater IOL weight than Group A (Group B vs. Group A: 28.31 ± 2.01 mg vs. 25.71 ± 4.62 mg, P < 0.001). Correspondingly, Group B presented significantly greater overall and inferior decentration than Group A, especially for low and medium IOL power (all P < 0.05). In both groups, overall and vertical decentration was significantly correlated with IOL weight (all P < 0.05). Group B showed a significantly greater ACO area than Group A (P < 0.05). Multivariate analysis showed that decentration in Group A was affected by IOL weight, while decentration in Group B was affected by IOL weight and AL.

Conclusions

Higher IOL weight may lead to greater long-term IOL decentration in highly myopic eyes, while the haptic design may play a role in anterior capsular contraction.
Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer
Authors: He Rong , Zhang Meiling , He Lian , Huang Jiabin , Man Changfeng , Wang Xiaoyan , Lang Yakun , Fan Yu
Published: April 2022

Background

Necroptosis, is intimately linked to tumor development and prognosis and has been considered as a target for anticancer therapy. However, the role of necroptosis-related genes (NRGs) in colon cancer is unclear.

Methods

In the present study, we screened 76 NRGs from previous studies and described the landscape of transcriptomic and genetic variation of NRGs in colon cancer (CC) patient samples. Molecular subtypes of necroptosis in colon cancer were identified by clustering analysis, and these molecular subtypes were linked to patient prognosis and TME cell infiltration characteristics. Then, the NRS-score for predicting overall survival (OS) was built based on the TCGA database and validated in the GSE39582 cohort for its predictive power in CC patients. Besides, the ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between NRS-score and tumor immune microenvironment.

Results

We identified two molecular subtypes associated with necroptosis in CC, which have diverse prognosis and immune microenvironment characteristics. Based on the differentially expressed genes between the two molecular subtypes, we further developed a necroptosis risk score signature, referred to as NRS-score. High NRS-score was associated with poor prognosis in CC through immunosuppressive microenvironment and immune escape mechanisms. The nomogram based on NRS-score showed excellent ability to predict prognosis. In addition, NRS-score presented a positive correlation with tumor mutational burden (TMB) and immune checkpoint blockade (ICB) expression and was closely correlated with multiple anticancer agent susceptibility.

Conclusion

This work revealed a close relationship between necroptosis and the prognosis and immune microenvironment of colon cancer. The NRS-score based on the 8-gene signature may be used to predict the sensitivity of immunotherapy and chemotherapy in colon cancer patients, and provides a foundation for future studies targeting necroptosis and its immune microenvironment.
Activation of Complement Pathways in Kidney Tissue May Mediate Tubulointerstitial Injury in Diabetic Nephropathy
Authors: Jiang Shimin , Jiao Yuanyuan , Zou Guming , Gao Hongmei , Zhuo Li , Li Wenge
Published: April 2022

Introduction

Key genes involved in tubulointerstitial injury may influence the development and progression of diabetic nephropathy (DN). We investigated whether complement-related genes are linked to the mechanism underlying tubulointerstitial injury in DN.

Methods

We analyzed the microarray data of 17 tubulointerstitial tissue samples from DN patients and 21 normal controls from the Gene Expression Omnibus. A gene co-expression network was constructed, and genes were divided into modules by weighted gene co-expression network analysis (WGCNA). We also investigated the association of C3 and C1q deposits in kidney tissues with a composite outcome of end-stage renal disease or a 50% reduction in the estimated glomerular filtration rate (eGFR) in DN patients. Finally, we performed immunohistochemical analyses of C3, C1q, C5b-9, mannose-binding lectin (MBL), and factor B in kidney tissues.

Results

Nine co-expression modules were constructed using 12,075 genes from the 38 human tubulointerstitial tissue samples. Black module with more genes was positively correlated with tubulointerstitial injury in DN. C3, one of the top 10 genes in tubulointerstitial injury, was verified in an independent dataset; C3 was significantly overexpressed in tubulointerstitial tissue from patients with DN compared to the normal controls. The mRNA level of C3 in renal tubulointerstitium was negatively correlated with eGFR in DN patients (r = −0.75; p = 0.001). Analysis of the follow-up data of 54 DN patients demonstrated that codeposits of C3 and C1q in kidney tissues were independently associated with the renal outcome in DN (hazard ratio, 2.3, 95% confidence interval, 1.01–5.2, p < 0.05). Immunohistochemical analysis showed that patients with higher C1q, C3, C5b-9, MBL, or factor B expression in renal tubulointerstitium were more likely to progress to kidney failure.

Conclusion

Local complement activation of the classical, lectin and alternative pathways appears linked to tubulointerstitial injury and disease progression in DN.
Physical Activity and Mortality in Patients With Chronic Kidney Disease: A Protocol for Systematic Review and Dose-Response Meta-Analysis
Authors: Zhang Fan , Wang Hui , Huang Liuyan , Bai Yan
Published: April 2022

Objective

To examine the dose-response associations between total physical activity, different intensity of physical activity, and all-cause mortality in patients with chronic kidney disease (CKD).

Methods and Analysis

PubMed, Embase, Web of Science, and the Cochrane library will be searched from inception to June 2022. Only cohort studies assessing physical activity associations with all-cause mortality among CKD patients will be considered for inclusion. The quality of included cohort studies will be evaluated according to the Newcastle-Ottawa Scale (NOS). The robust error meta-regression (REMR) model will be used to establish dose-response relationships between physical activity and mortality. Additional statistical analysis including Egger's test, subgroup analysis, sensitivity analysis. The strengths of evidence will be evaluated with the Grading of Recommendation, Assessment, Development, and Evaluation approach.

Ethics and Dissemination

Ethics approval is not required as no private information from individuals is collected.

PROSPERO Registration Number

CRD 42021283630.
Artificial Intelligence-Enabled Electrocardiogram Predicted Left Ventricle Diameter as an Independent Risk Factor of Long-Term Cardiovascular Outcome in Patients With Normal Ejection Fraction
Authors: Chen Hung-Yi , Lin Chin-Sheng , Fang Wen-Hui , Lee Chia-Cheng , Ho Ching-Liang , Wang Chih-Hung , Lin Chin
Published: April 2022

Background

Heart failure (HF) is a global disease with increasing prevalence in an aging society. However, the survival rate is poor despite the patient receiving standard treatment. Early identification of patients with a high risk of HF is important but challenging. Left ventricular end-diastolic diameter (LV-D) increase was an independent risk factor of HF and adverse cardiovascular (CV) outcomes. In this study, we aimed to develop an artificial intelligence (AI) enabled electrocardiogram (ECG) system to detect LV-D increase early.

Objective

We developed a deep learning model (DLM) to predict left ventricular end-diastolic and end-systolic diameter (LV-D and LV-S) with internal and external validations and investigated the relationship between ECG-LV-D and echocardiographic LV-D and explored the contributions of ECG-LV-D on future CV outcomes.

Methods

Electrocardiograms and corresponding echocardiography data within 7 days were collected and paired for DLM training with 99,692 ECGs in the development set and 20,197 ECGs in the tuning set. The other 7,551 and 11,644 ECGs were collected from two different hospitals to validate the DLM performance in internal and external validation sets. We analyzed the association and prediction ability of ECG-LVD for CV outcomes, including left ventricular (LV) dysfunction, CV mortality, acute myocardial infarction (AMI), and coronary artery disease (CAD).

Results

The mean absolute errors (MAE) of ECG-LV-D were 5.25/5.29, and the area under the receiver operating characteristic (ROC) curves (AUCs) were 0.8297/0.8072 and 0.9295/0.9148 for the detection of mild (56 ≦ LV-D < 65 mm) and severe (LV-D ≧ 65 mm) LV-D dilation in internal/external validation sets, respectively. Patients with normal ejection fraction (EF) who were identified as high ECHO-LV-D had the higher hazard ratios (HRs) of developing new onset LV dysfunction [HR: 2.34, 95% conference interval (CI): 1.78–3.08], CV mortality (HR 2.30, 95% CI 1.05–5.05), new-onset AMI (HR 2.12, 95% CI 1.36–3.29), and CAD (HR 1.59, 95% CI 1.26–2.00) in the internal validation set. In addition, the ECG-LV-D presents a 1.88-fold risk (95% CI 1.47–2.39) on new-onset LV dysfunction in the external validation set.

Conclusion

The ECG-LV-D not only identifies high-risk patients with normal EF but also serves as an independent risk factor of long-term CV outcomes.
Current Trends in Circulating Biomarkers for Melanoma Detection
Authors: Huang Nancy , Lee Katie J. , Stark Mitchell S.
Published: April 2022

Melanomas have increased in global incidence and are the leading cause of skin cancer deaths. Whilst the majority of early-stage, non-metastatic melanomas can be cured with surgical excision alone, ~5% of patients with early melanomas will experience recurrence following a variable disease-free interval and progression to metastatic melanoma and ultimately death. This is likely because of primary tumor heterogeneity and progressive clonal divergency resulting in the growth of more aggressive tumor populations. Liquid biomarkers have the advantage of real-time, non-invasive longitudinal monitoring of tumor burden and heterogeneity over tissue markers. Currently, the only serological marker used in the staging and monitoring of melanoma is serum lactate dehydrogenase, which is not sufficiently specific or sensitive, and is not used routinely in all centers. An ideal melanoma biomarker would be used to identify patients who are at high-risk of primary melanoma, screen for relapse, detect early-stage melanoma, provide treatment outcomes to personalize systemic treatment, follow tumor heterogeneity, provide prognostic data before, during and after treatment, and monitor response to treatment. This review provides a summary of the current research in this field with a specific focus on circulating tumor cells, circulating tumor DNA, microRNA, and extracellular vesicles which may serve to suit these goals.
Health-Related Quality of Life Evaluation Using the Short Form-36 in Patients With Human T-Lymphotropic Virus Type 1-Associated Myelopathy
Authors: Kimura Miyuna , Yamauchi Junji , Sato Tomoo , Yagishita Naoko , Araya Natsumi , Aratani Satoko , Tanabe Kenichiro , Horibe Erika , Watanabe Toshiki , Coler-Reilly Ariella , Nagasaka Misako , Akasu Yukari , Kaburagi Kei , Kikuchi Takayuki , Shibata Soichiro , Matsumoto Hirofumi , Koseki Akihito , Inoue Soichiro , Takata Ayako , Yamano Yoshihisa
Published: April 2022

Background

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) is a neuroinflammatory disease, causing various neurological symptoms, including motor, sensory, and bladder and bowel dysfunctions. This study was designed to reveal the impact of HAM and related symptoms on health-related quality of life (HRQoL).

Methods

We analyzed the Short Form-36 (SF-36) and clinical data of 538 patients with HAM registered in the HAM-net, a nationwide patient registry for HAM in Japan. HRQoL was evaluated using the SF-6D (a health state utility value calculated from the SF-36) and eight SF-36 subscales. A general liner model was used to estimate the impact of major HAM-related symptoms, including gait dysfunction, sensory disturbance in the legs (pain and numbness), urinary dysfunction, and constipation, on the SF-6D and SF-36 subscale scores.

Results

The mean age and disease duration were 62.0 and 16.5 years, respectively. Of the patients, 73.2% needed walking aid; 42.7 and 67.1% had leg pain and numbness, respectively; 92.1% had urinary dysfunction; and 77.9% had constipation. The mean SF-6D score was 0.565, which was significantly lower than the national average (0.674 in the 60–69 years age group; p < 0.001), exceeding the minimal important difference (0.05–0.1). All the major symptoms were significantly associated with a decrease in the SF-6D score. The SF-36 subscale scores were significantly lower than the national standard of 50 (p ≤ 0.001), except for mental health (MH). Gait dysfunction was associated with lower scores in physical functioning (PF), limitations on role functioning because of physical health, bodily pain, general health perception (GH), vitality (VT), and social functioning; however, no association was observed between gait dysfunction and limitations on role functioning because of emotional problems and MH. Meanwhile, sensory disturbance in the legs was associated with a decrease in scores in all subscales. Urinary dysfunction was associated with worse PF, GH, VT, and MH. Constipation was associated only with PF.

Conclusion

HRQoL of patients with HAM was worse than that of the general population and was associated with all major symptoms. Thus, patients should be comprehensively managed to achieve better HRQoL.
Evaluation of an Artificial Intelligence System for the Detection of Diabetic Retinopathy in Chinese Community Healthcare Centers
Authors: Dong Xiuqing , Du Shaolin , Zheng Wenkai , Cai Chusheng , Liu Huaxiu , Zou Jiangfeng
Published: April 2022

Objective

To evaluate the sensitivity and specificity of a Comprehensive Artificial Intelligence Retinal Expert (CARE) system for detecting diabetic retinopathy (DR) in a Chinese community population.

Methods

This was a cross-sectional, diagnostic study. Participants with a previous diagnosis of diabetes from three Chinese community healthcare centers were enrolled in the study. Single-field color fundus photography was obtained and analyzed by the AI system and two ophthalmologists. Primary outcome measures included the sensitivity, specificity, positive predictive value, and negative predictive value with their 95% confidence intervals (CIs) of the AI system in detecting DR and diabetic macular edema (DME).

Results

In this study, 443 subjects (848 eyes) were enrolled, and 283 (63.88%) were men. The mean age was 52.09 (11.51) years (range 18–82 years); 266 eyes were diagnosed with any DR, 233 with more-than-mild diabetic retinopathy (mtmDR), 112 with vision-threatening diabetic retinopathy (vtDR), and 57 with DME. The image ability of the AI system was as high as 99.06%, whereas its sensitivity and specificity varied significantly in detecting DR with different severities. The sensitivity/specificity to detect any DR was 75.19% (95%CI 69.47–80.17)/93.99% (95%CI 91.65–95.71), mtmDR 78.97% (95%CI 73.06–83.90)/92.52% (95%CI 90.07–94.41), vtDR 33.93% (95%CI 25.41–43.56)/97.69% (95%CI 96.25–98.61), and DME 47.37% (95%CI 34.18–60.91)/93.99% (95%CI 91.65–95.71).

Conclusions

This multicenter cross-sectional diagnostic study noted the safety and reliability of the CARE system for DR (especially mtmDR) detection in Chinese community healthcare centers. The system may effectively solve the dilemma faced by Chinese community healthcare centers: due to the lack of ophthalmic expertise of primary physicians, DR diagnosis and referral are not timely.
Effect of Photoreduction of Semiconducting Iron Mineral—Goethite on Microbial Community in the Marine Euphotic Zone
Authors: Liu Jia , Ge Xiao , Ding Hongrui , Yang Shanshan , Sun Yuan , Li Yanzhang , Ji Xiang , Li Yan , Lu Anhuai
Published: April 2022

Marine euphotic zone is the pivotal region for interplay of light-mineral–microorganism and elements cycle, in which semiconducting minerals exist widely and iron-bearing goethite is a typical and widespread one. In this work, we have conducted in-depth researches on the effect of ferrous [Fe(II)] ions dissolved by photoreduction of goethite on microbial community structure and diversity. The mineral phase, structure and morphology of synthesized goethite were characterized by Raman, X-ray diffraction (XRD), energy disperse spectroscopy (EDS), environmental scanning electron microscope (ESEM), and atomic force microscope (AFM). Photoelectrochemical measurements tested photoelectric response and redox activity of goethite, having proved its significant property of photoelectric response with 44.11% increment of the average photocurrent density relative to the dark current density. The photoreduction experiments of goethite were conducted under light condition in simulated seawater. It has suggested the photoreduction of goethite could occur and Fe(III) was reduced to Fe(II). The dissolved Fe(II) from the photoreduction of goethite under light condition was nearly 11 times than that group without light after a 10-day reaction. Furthermore, results of microbial community sequencing analysis indicated that dissolved Fe(II) could affect the structure and regulate the decrease of microbial community diversity. The emergence of dominant bacteria associated with iron oxidation and transport protein has suggested their obvious selectivity and adaptability in the environment with adding dissolved Fe(II). This work revealed the photoreduction process of semiconducting goethite was remarkable, giving rise to a non-negligible dissolved Fe(II) and its selective effect on the structure, diversity, as well as the function of microbial community. This light-induced interaction between minerals and microorganisms may also further regulate correlative metabolic pathways of carbon cycle in the marine euphotic zone.
NNAN: Nearest Neighbor Attention Network to Predict Drug–Microbe Associations
Authors: Zhu Bei , Xu Yi , Zhao Pengcheng , Yiu Siu-Ming , Yu Hui , Shi Jian-Yu
Published: April 2022

Many drugs can be metabolized by human microbes; the drug metabolites would significantly alter pharmacological effects and result in low therapeutic efficacy for patients. Hence, it is crucial to identify potential drug–microbe associations (DMAs) before the drug administrations. Nevertheless, traditional DMA determination cannot be applied in a wide range due to the tremendous number of microbe species, high costs, and the fact that it is time-consuming. Thus, predicting possible DMAs in computer technology is an essential topic. Inspired by other issues addressed by deep learning, we designed a deep learning-based model named Nearest Neighbor Attention Network (NNAN). The proposed model consists of four components, namely, a similarity network constructor, a nearest-neighbor aggregator, a feature attention block, and a predictor. In brief, the similarity block contains a microbe similarity network and a drug similarity network. The nearest-neighbor aggregator generates the embedding representations of drug–microbe pairs by integrating drug neighbors and microbe neighbors of each drug–microbe pair in the network. The feature attention block evaluates the importance of each dimension of drug–microbe pair embedding by a set of ordinary multi-layer neural networks. The predictor is an ordinary fully-connected deep neural network that functions as a binary classifier to distinguish potential DMAs among unlabeled drug–microbe pairs. Several experiments on two benchmark databases are performed to evaluate the performance of NNAN. First, the comparison with state-of-the-art baseline approaches demonstrates the superiority of NNAN under cross-validation in terms of predicting performance. Moreover, the interpretability inspection reveals that a drug tends to associate with a microbe if it finds its top-l most similar neighbors that associate with the microbe.
Regulatory Role of Host MicroRNAs in Flaviviruses Infection
Authors: Cai Wenjun , Pan Yuhong , Cheng Anchun , Wang Mingshu , Yin Zhongqiong , Jia Renyong
Published: April 2022

MicroRNAs (miRNAs) are small non-coding RNA that affect mRNA abundance or translation efficiency by binding to the 3′UTR of the mRNA of the target gene, thereby participating in multiple biological processes, including viral infection. Flavivirus genus consists of small, positive-stranded, single-stranded RNA viruses transmitted by arthropods, especially mosquitoes and ticks. The genus contains several globally significant human/animal pathogens, such as Dengue virus, Japanese encephalitis virus, West Nile virus, Zika virus, Yellow fever virus, Tick-borne encephalitis virus, and Tembusu virus. After flavivirus invades, the expression of host miRNA changes, exerting the immune escape mechanism to create an environment conducive to its survival, and the altered miRNA in turn affects the life cycle of the virus. Accumulated evidence suggests that host miRNAs influence flavivirus replication and host–virus interactions through direct binding of viral genomes or through virus-mediated host transcriptome changes. Furthermore, miRNA can also interweave with other non-coding RNAs, such as long non-coding RNA and circular RNA, to form an interaction network to regulate viral replication. A variety of non-coding RNAs produced by the virus itself exert similar function by interacting with cellular RNA and viral RNA. Understanding the interaction sites between non-coding RNA, especially miRNA, and virus/host genes will help us to find targets for antiviral drugs and viral therapy.
Ligand-Bound Forced Degradation as a Strategy to Generate Functionally Relevant Analytical Challenge Materials for Assessment of CQAs
Authors: Giddens John P. , Schiel John E.
Published: April 2022

Therapeutic monoclonal antibodies (mAbs) contain a variety of amino acids that are susceptible to enzymatic, chemical, and physical modifications. These modifications can happen throughout production, purification, formulation, and storage and many are known to affect the biological activity of a mAb. Methods that are able to characterize and evaluate these attributes are critical in order to understand how they might alter biological activity. Methods capable of site-specific monitoring of these critical quality attributes are extremely valuable to biopharmaceutical research but also require well-defined materials with site-specific attribute modifications. Here, we describe the development and application of a strategy to generate functionally relevant analytical challenge materials that have unique site-specific attributes. This method involves the use of a ligand that is bound to the mAb during oxidative stress resulting in unique oxidation patterns with some methionine residues protected while others are exposed to oxidation. These unique materials were used to develop a rapid surface plasmon resonance (SPR) assay that could detect methionine oxidation in both the Fab and Fc regions using specific molecular probes. The addition of uniquely oxidized materials to our data set enabled us to determine specific methionine residues vital to binding. Further analysis showed that antibody oxidation could also be rapidly detected in multiple domains from qualitative thermal melting using intrinsic tryptophan fluorescence. Methionine oxidation of an antibody was explored in this study, but we envision this method could be useful to explore structure function relationships of a variety of antibody modifications and modifications to other biologically relevant protein drugs.
Structural Characterization of the Full-Length Anti-CD20 Antibody Rituximab
Authors: Belviso Benny Danilo , Mangiatordi Giuseppe Felice , Alberga Domenico , Mangini Vincenzo , Carrozzini Benedetta , Caliandro Rocco
Published: April 2022

Rituximab, a murine–human chimera, is the first monoclonal antibody (mAb) developed as a therapeutic agent to target CD20 protein. Its Fab domain and its interaction with CD20 have been extensively studied and high-resolution atomic models obtained by X-ray diffraction or cryo-electron microscopy are available. However, the structure of the full-length antibody is still missing as the inherent protein flexibility hampers the formation of well-diffracting crystals and the reconstruction of 3D microscope images. The global structure of rituximab from its dilute solution is here elucidated by small-angle X-ray scattering (SAXS). The limited data resolution achievable by this technique has been compensated by intensive computational modelling that led to develop a new and effective procedure to characterize the average mAb conformation as well as that of the single domains. SAXS data indicated that rituximab adopts an asymmetric average conformation in solution, with a radius of gyration and a maximum linear dimension of 52 Å and 197 Å, respectively. The asymmetry is mainly due to an uneven arrangement of the two Fab units with respect to the central stem (the Fc domain) and reflects in a different conformation of the individual units. As a result, the Fab elbow angle, which is a crucial determinant for antigen recognition and binding, was found to be larger (169°) in the more distant Fab unit than that in the less distant one (143°). The whole flexibility of the antibody has been found to strongly depend on the relative inter-domain orientations, with one of the Fab arms playing a major role. The average structure and the amount of flexibility has been studied in the presence of different buffers and additives, and monitored at increasing temperature, up to the complete unfolding of the antibody. Overall, the structural characterization of rituximab can help in designing next-generation anti-CD20 antibodies and finding more efficient routes for rituximab production at industrial level.
Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders
Authors: Taghavi Amirhossein , Yildirim Ilyas
Published: April 2022

Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington’s disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational landscapes adopted by 3×3, 2×2, and 1×1 internal loops observed in RNA AUUCU, CCUG, CAG, and CUG repeat expansions using model systems having biologically relevant repeat sizes. We show that the conformational variability experienced by these loops is more complex than previous reports where a variety of unconventional hydrogen bonds are formed. At the global scale, strong bending propensity was observed in r(AUUCU)10, r(CCUG)15, r(CAG)20, and r(CUG)20, and, to a lesser extent, in r(AUUCU)4, r(CCUG)10, r(CAG)10, and r(CUG)10. Furthermore, RNA CAG repeats exhibit a tendency toward bent states with more than 50% of observed conformations having bending angles greater than 50°, while RNA CUG repeats display relatively linear-like conformations with extremely bent conformations accounting for less than 25% of the observed structures. Conformations experienced by RNA AUUCU repeats are a combination of strongly bent and kinked structures. The bent states in RNA CCUG repeats mostly fall into the moderately bent category with a marginal ensemble experiencing extreme bending. The general pattern observed in all the bent structures indicates the collapse of the major groove width as the mechanical trigger for bending, which is caused by alteration of base pair step parameters at multiple locations along the RNA due to local distortions at the loop sites. Overextension is also observed in all the RNA repeats that is attributed to widening of the major groove width as well as undertwisting phenomenon. This information and the rich structural repository could be applied for structure based small molecule design targeting disease-causing RNAs. The bending propensities of these constructs, at the global level, could also have implications on how expanded RNA repeats interact with proteins.
Identification of Novel Immune Cell-Relevant Therapeutic Targets and Validation of Roles of TK1 in BMSCs of Systemic Lupus Erythematosus
Authors: Chen Fangru , Meng Jian , Yan Wenjie , Wang Mengjiao , Jiang Yunfei , Gao Jintao
Published: April 2022

Objective: Systemic lupus erythematosus (SLE) displays the characteristics of abnormal activity of the immune system, contributing to diverse clinical symptoms. Herein, this study was conducted for discovering novel immune cell-relevant therapeutic targets.

Methods: The abundance of diverse immune cells was estimated in PBMCs of SLE and healthy controls from the GSE50772 dataset with CIBERSORT approach. Immune cell-relevant co-expression modules were screened with WGCNA and relevant characteristic genes were determined with LASSO algorithm. Inflammatory chemokines were measured in serum of twenty SLE patients and twenty controls through ELISA. Bone marrow mesenchymal stem cells (BMSCs) were isolated and TK1 expression was measured in BMSCs through RT-qPCR and western blotting. TK1-overexpressed and TK-1-silenced BMSCs of SLE were conducted and apoptosis and cell cycle were measured with flow cytometry. Apoptosis-, cell cycle- and senescence-relevant proteins were tested with western blotting.

Results: We determined three co-expression modules strongly linked to immune cells. Five characteristic genes (CXCL1, CXCL2, CXCL8, CXCR1 and TK1) were screened and ROC curves proved the excellent diagnostic performance of this LASSO model. Inflammatory chemokines presented widespread up-regulations in serum of Systemic lupus erythematosus patients, demonstrating the activation of inflammatory response. TK1 expression was remarkably elevated in SLE BMSCs than controls. TK1 overexpression enhanced IL-1β expression, apoptosis, cell cycle arrest, and senescent phenotypes of SLE BMSCs and the opposite results were proved in TK1-silenced SLE BMSCs.

Conclusion: Collectively, our findings demonstrate that silencing TK1 alleviates inflammation, growth arrest and senescence in BMSCs of SLE, which highlights TK1 as a promising therapeutic target against SLE.
The Effect of Endolymphatic Hydrops and Mannitol Dehydration Treatment on Guinea Pigs
Authors: Wang Shu-Qi , Li Chen-Long , Xu Jing-Qi , Chen Li-Li , Xie You-Zhou , Dai Pei-Dong , Ren Liu-Jie , Yao Wen-Juan , Zhang Tian-Yu
Published: April 2022

Background

Endolymphatic hydrops (EH) is considered as the pathological correlate of Menière’s disease (MD) and cause of hearing loss. The mechanism of EH, remaining unrevealed, poses challenges for formalized clinical trials.

Objective

This study aims to investigate the development of hearing loss, as well as the effect of dehydration treatment on EH animal models.

Methods

In this study, different severity EH animal models were created. The laser Doppler vibrometer (LDV) and auditory brainstem responses (ABR) were used to study the effects of EH and the dehydration effects of mannitol. The LDV was used to measure the vibration of the round window membrane (RWM) reflecting the changes in inner ear impedance. ABR was used to evaluate the hearing changes. Furthermore, tissue section and scanning electron microscopy (SEM) observations were used to analyze the anatomical change to the cochlea and outer hair cells.

Results

The RWM vibrations decreased with the severity of EH, indicating an increase in the cochlear impedance. The dehydration therapy lowered the impedance to restore acoustic transduction in EH 10- and 20-day animal models. Simultaneously, the ABR thresholds increased in EH models and were restored after dehydration. Moreover, a difference in the hearing was found between ABR and LDV results in severe EH animal models, and the dehydration therapy was less effective, indicating a sensorineural hearing loss (SNHL).

Conclusion

Endolymphatic hydrops causes hearing loss by increasing the cochlear impedance in all tested groups, and mannitol dehydration is an effective therapy to restore hearing. However, SNHL occurs for the EH 30-day animal models, limiting the effectiveness of dehydration. Our results suggest the use of dehydrating agents in the early stage of EH.
Trends in the Incidence and Risk Factors of Pregnancy-Associated Stroke
Authors: Ijäs Petra
Published: April 2022

Pregnancy is a female-specific risk factor for stroke. Although pregnancy-associated stroke (PAS) is a rare event, PAS leads to considerable maternal mortality and morbidity. It is estimated that 7.7–15% of all maternal deaths worldwide are caused by stroke and 30–50% of surviving women are left with persistent neurological deficits. During last decade, several studies have reported an increasing incidence of PAS. The objective of this review is to summarize studies on time trends of PAS in relation to trends in the prevalence of stroke risk factors in pregnant women. Seven retrospective national healthcare register-based cohort studies from the US, Canada, UK, Sweden, and Finland were identified. Five studies from the US, Canada, and Finland reported an increasing trend of PAS. Potential biases include more sensitive diagnostics and improved stroke awareness among pregnant women and professionals toward the end of the study period. However, the concurrent increase in the prevalence of several stroke risk factors among pregnant women, particularly advanced age, hypertensive disorders of pregnancy, diabetes, and obesity, indicate that the findings are likely robust and should be considered seriously. To reduce stroke in pregnancy, increased awareness among all medical specialties and pregnant women on the importance of risk-factor management during pregnancy and stroke symptoms is necessary. Important preventive measures include counseling for smoking cessation and substance abuse, treatment of hypertensive disorders of pregnancy, use of aspirin in women at high risk for developing preeclampsia, and antithrombotic medication and pregnancy surveillance for women with high-risk conditions. Epidemiological data from countries with a high risk-factor burden are largely missing. National and international registries and prospective studies are needed to increase knowledge on the mechanisms, risk factors, management, and future implications for the health of women who experience this rare but devastating complication of pregnancy.
Isolated Otolith Dysfunction in Persistent Postural-Perceptual Dizziness
Authors: Murofushi Toshihisa , Nishimura Koji , Tsubota Masahito
Published: April 2022

The aims of this study were to investigate otolith dysfunction, especially isolated otolith dysfunction (with preserved semicircular canal function) in persistent postural-perceptual dizziness (PPPD) patients. Twenty-one patients who had been diagnosed with PPPD were enrolled in this study. The subjects filled out questionnaires [the Dizziness Handicap Inventory (DHI) and the Niigata PPPD Questionnaire (NPQ)] and underwent vestibular evoked myogenic potential (VEMP) tests, video head-impulse tests (vHIT), and stabilometry. Among the 21 subjects with PPPD, 9 showed isolated otolith dysfunction, 4 exhibited both otolith dysfunction and semicircular canal dysfunction, and 2 demonstrated isolated semicircular canal dysfunction. Six subjects exhibited normal VEMP and vHIT results. Concerning the subjects' questionnaire scores and stabilometric parameters, there were no significant differences among subgroups when the subjects were classified according to their VEMP and vHIT results while stabilometric parameters obtained in PPPD subjects were significantly increased than published data of healthy subjects. As precipitating conditions for PPPD, vestibular neuritis was the most frequent and the second most was idiopathic otolithic vertigo. In conclusion, the majority of PPPD patients had otolith dysfunction, and most of them showed isolated otolith dysfunction. Idiopathic otolithic vertigo can be a precipitating factor of PPPD. While otolith dysfunction may be associated with initiation of PPPD symptoms, PPPD symptoms are also considered to be associated with other dysfunctions of the sensory processing system.