bluuebunny/crossref_metadata_2025 huggingface dataset:
XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil
Authors: Castro Ligia Pereira , Batista-Vieira Danilo , de Souza Tiago Antonio , Timoteo Ana Rafaela de Souza , Coutinho Jessica Dayanna Landivar , Pinheiro de Almeida Isabel Cristina , Henriques Sheila Ramos de Miranda , Azevedo Fabio Medeiros de , Rosa Reginaldo Cruz Alves , Kannouche Patricia L , Sarasin Alain , Menck Carlos Frederico Martins , Petta Tirzah Braz
Published: January 2022

Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.
Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study
Authors: Mu Changqing , Zhao Yating , Han Chen , Tian Dandan , Guo Na , Zhang Chenguang , Zhu Ruixia , Zhang Xiaoqian , Zhang Jian , Liu Xu
Published: January 2022

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.
Influence of T Cell-Mediated Immune Surveillance on Somatic Mutation Occurrences in Melanoma
Authors: Jiang Chongming , Schaafsma Evelien , Hong Wei , Zhao Yanding , Zhu Ken , Chao Cheng-Chi , Cheng Chao
Published: January 2022

Background

Neoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.

Methods

We investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.

Results

Our results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.

Conclusions

These results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.
Exhausted and Apoptotic BALF T Cells in Proinflammatory Airway Milieu at Acute Phase of Severe Mycoplasma Pneumoniae Pneumonia in Children
Authors: Chen Xi , Liu Fang , Zheng Baoying , Kang Xiaohui , Wang Xiaolin , Mou Wenjun , Zhang Hui , Jiao Anxia , Zhao Shunying , Gui Jingang
Published: January 2022

Severe mycoplasma pneumoniae pneumonia (MPP) in children presents with serious clinical complications. Without proper and prompt intervention, it could lead to deadly consequences. Dynamics of the inflammatory airway milieu and activation status of immune cells were believed to be the hallmark of the pathogenesis and progress of the disease. In this study, by employing the T-cell sorting and mRNA microarray, we were able to define the main feature of the chemokine/cytokine expression and the unique characteristics of T cells in the bronchoalveolar lavage fluid (BALF) from severe MPP patients at acute phase. Our study for the first time delineated the molecular changes in isolated BALF T cells in severe MPP children with respect to the cytokine/chemokine expression, cell activation, exhaustion, and apoptosis. By comparing the BALF aqueous expression of cytokines/chemokines with that in sorted T cells, our data give a preliminary clue capable of finishing out the possible cell source of the proinflammatory cytokines/chemokines from the BALF mixture. Meanwhile, our data provide a distinctively pellucid expression profile particularly belonging to the isolated BALF T cells demonstrating that in the inflammatory airway, overactivated T cells were exhausted and on the verge of apoptotic progress.
Tree Shrew Is a Suitable Animal Model for the Study of Epstein Barr Virus
Authors: Xia Wei , Chen Honglin , Feng Yiwei , Shi Nan , Huang Zongjian , Feng Qingyuan , Jiang Xu , He Guangyao , Xie Mao , Lai Yongjin , Wang Zhi , Yi Xiang , Tang Anzhou
Published: January 2022

Epstein-Barr virus (EBV) is a human herpesvirus that latently infects approximately 95% of adults and is associated with a spectrum of human diseases including Infectious Mononucleosis and a variety of malignancies. However, understanding the pathogenesis, vaccines and antiviral drugs for EBV-associated disease has been hampered by the lack of suitable animal models. Tree shrew is a novel laboratory animal with a close phylogenetic relationship to primates, which is a critical advantage for many animal models for human disease, especially viral infections. Herein, we first identified the key residues in the CR2 receptor that bind the gp350 protein and facilitate viral entry. We found that tree shrew shares 100% sequence identity with humans in these residues, which is much higher than rabbits (50%) and rats (25%). In vitro analysis showed that B lymphocytes of tree shrews are susceptible to EBV infection and replication, as well as EBV-enhanced cell proliferation. Moreover, results of in vivo experiments show that EBV infection in tree shrews resembles EBV infection in humans. The infected animals exhibited transient fever and loss of weight accompanied by neutropenia and high viremia levels during the acute phase of the viral infection. Thereafter, tree shrews acted as asymptomatic carriers of the virus in most cases that EBV-related protein could be detected in blood and tissues. However, a resurgence of EBV infection occurred at 49 dpi. Nanopore transcriptomic sequencing of peripheral blood in EBV-infected animals revealed the dynamic changes in biological processes occurring during EBV primary infection. Importantly, we find that neutrophil function was impaired in tree shrew model as well as human Infectious Mononucleosis datasets (GSE85599 and GSE45918). In addition, retrospective case reviews suggested that neutropenia may play an important role in EBV escaping host innate immune response, leading to long-term latent infection. Our findings demonstrated that tree shrew is a suitable animal model to evaluate the mechanisms of EBV infection, and for developing vaccines and therapeutic drugs against EBV.
Metabolic Enzyme Triosephosphate Isomerase 1 and Nicotinamide Phosphoribosyltransferase, Two Independent Inflammatory Indicators in Rheumatoid Arthritis: Evidences From Collagen-Induced Arthritis and Clinical Samples
Authors: Lei Ming , Tao Meng-Qing , Wu Yi-Jin , Xu Liang , Yang Zhe , Li Yan , Olatunji Opeyemi Joshua , Wang Xiao-Wan , Zuo Jian
Published: January 2022

Metabolic intervention is a novel anti-rheumatic approach. The glycolytic regulator NAMPT has been identified as a therapeutic target of rheumatoid arthritis (RA), while other metabolic regulators coordinating NAMPT to perpetuate inflammation are yet to be investigated. We continuously monitored and validated expression changes of Nampt and inflammatory indicators in peripheral while blood cells from rats with collagen-induced arthritis (CIA). Gene transcriptional profiles of Nampt+ and Nampt++ samples from identical CIA rats were compared by RNA-sequencing. Observed gene expression changes were validated in another batch of CIA rats, and typical metabolic regulators with persistent changes during inflammatory courses were further investigated in human subjects. According to expression differences of identified genes, RA patients were assigned into different subsets. Clinical manifestation and cytokine profiles among them were compared afterwards. Nampt overexpression typically occurred in CIA rats during early stages, when iNos and Il-1β started to be up-regulated. Among differentially expressed genes between Nampt+ and Nampt++ CIA rat samples, changes of Tpi1, the only glycolytic enzyme identified were sustained in the aftermath of acute inflammation. Similar to NAMPT, TPI1 expression in RA patients was higher than general population, which was synchronized with increase in RFn as well as inflammatory monocytes-related cytokines like Eotaxin. Meanwhile, RANTES levels were relatively low when NAMPT and TPI1 were overexpressed. Reciprocal interactions between TPI1 and HIF-1α were observed. HIF-1α promoted TPI1 expression, while TPI1 co-localized with HIF-1α in nucleus of inflammatory monocytes. In short, although NAMPT and TPI1 dominate different stages of CIA, they similarly provoke monocyte-mediated inflammation.
Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV
Authors: Fuseini Hubaida , Smith Rita , Nochowicz Cindy H. , Simmons Joshua D. , Hannah LaToya , Wanjalla Celestine N. , Gabriel Curtis L. , Mashayekhi Mona , Bailin Samuel S. , Castilho Jessica L. , Hasty Alyssa H. , Koethe John R. , Kalams Spyros A.
Published: January 2022

While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4+ T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m2, is positively correlated with greater CD4+ T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4+ T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4+ T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4+ T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4+ T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4+ T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4+ T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4+ T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4+ T reconstitution in PLWH initiating ART.
Replacement and Immunomodulatory Activities of 20% Subcutaneous Immunoglobulin Treatment: A Single-Center Retrospective Study in Autoimmune Myositis and CVID Patients
Authors: Danieli Maria Giovanna , Verga Jacopo Umberto , Mezzanotte Cristina , Terrenato Irene , Svegliati Silvia , Bilo Maria Beatrice , Moroncini Gianluca
Published: January 2022

Background

Immunoglobulin (Ig) replacement therapy represents a life-saving treatment in primary antibody deficiencies. The introduction of subcutaneous Ig (SCIg) administration brings a major improvement in quality of life for patients, compared to the traditional intravenous administration. In recent years, an additional role has been proposed for Ig therapy for various inflammatory and immune-mediated diseases. Consequently, the use of SCIg has expanded from immunodeficiencies to immune-mediated diseases, such as polymyositis (PM) and dermatomyositis (DM). Given the rarity of these conditions, it is still difficult to evaluate the real impact of SCIg treatment on PM and DM, and additional data are constantly required on this topic, particularly for long-term treatments in real-life settings.

Aim

This study aimed to increase the knowledge about the anti-inflammatory and immunomodulatory effects of SCIg treatment for myositis. To this aim, a long-term evaluation of the effectiveness of 20% human SCIg treatment (20% SCIg, Hizentra®, CSL Behring) was carried out in patients with PM/DM in care at our Center. In addition, an evaluation of the 20% SCIg therapy in CVID patients was provided. This analysis, beside adding knowledge about the use of SCIg therapy in this real-life setting, was intended as a term of comparison, regarding the safety profile.

Results

Results support the beneficial effect and tolerability of long-term 20% SCIg therapy in PM/DM patients, reporting a significant improvement in creatine kinase levels, muscle strength, skin conditions, dysphagia, disease activity (MITAX score) and disability (HAQ-DI score). None of the patients reported systemic reactions. The duration of the reported local reactions was a few hours in 80% of the patients, and all resolved spontaneously. CVID patients reported an improvement in all the considered effectiveness parameters at the end of 20% SCIg therapy. The frequency of the adverse events reported by PM/DM patients was not different from what reported in CVID patients, where the use of SCIg therapy is more consolidated

Conclusions

This study suggests that 20% SCIg treatment represents a viable and safe treatment for PM/DM patients and a valid therapeutic alternative to IVIg, with important advantages for patients’ quality of life.
G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases
Authors: Li Nan , Shan Shan , Li Xiu-Qin , Chen Ting-Ting , Qi Meng , Zhang Sheng-Nan , Wang Zi-Ying , Zhang Ling-Ling , Wei Wei , Sun Wu-Yi
Published: January 2022

G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.
Injectable Hydrogel as a Unique Platform for Antitumor Therapy Targeting Immunosuppressive Tumor Microenvironment
Authors: Liu Yushuai , Geng Yuanyuan , Yue Beilei , Lo Pui-Chi , Huang Jing , Jin Honglin
Published: January 2022

Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment.
Mechanical Properties and Microstructure Evolution of Cemented Tailings Backfill Under Seepage Pressure
Authors: Ke Yuxian , Shen Yang , Qing Chen , Hu Kaijian , Wang Shi , Chen Qiusong , Guan Huadong
Published: January 2022

Cemented tailing backfill (CTB) in underground mine inevitably experiences seepage field, which complicates its mechanical behavior. In this study, the mechanical properties and microstructure characteristics of CTB under different seepage water pressures (SWPs) were investigated. The results show that, with the increase in SWP, the mechanical properties of CTB decrease, but the decreasing trend reduces gradually. Higher SWP leads the microstructure of CTB looser and more porous, and the largest proportion of pores initiated and propagated by SWP is micropores, which means the damage in CTB under seepage is mostly caused by micropores. Besides, the mechanical properties of CTB under seepage decrease exponentially with the increase in porosity and present linearly inverse proportional relation to the pore area fractal dimension. Results above indicate that SWP has a significant deterioration effect on the mechanical properties and microstructure of CTB. The research could not only extend the knowledge of mechanical properties and microstructure characteristics of CTB under seepage but also provide a theoretical reference for mechanical index determination and stability analysis of CTB in water-rich underground mines.
Machine Learning Prediction Model for Acute Renal Failure After Acute Aortic Syndrome Surgery
Authors: Li Jinzhang , Gong Ming , Joshi Yashutosh , Sun Lizhong , Huang Lianjun , Fan Ruixin , Gu Tianxiang , Zhang Zonggang , Zou Chengwei , Zhang Guowei , Qian Ximing , Qiao Chenhui , Chen Yu , Jiang Wenjian , Zhang Hongjia
Published: January 2022

Background

Acute renal failure (ARF) is the most common major complication following cardiac surgery for acute aortic syndrome (AAS) and worsens the postoperative prognosis. Our aim was to establish a machine learning prediction model for ARF occurrence in AAS patients.

Methods

We included AAS patient data from nine medical centers (n = 1,637) and analyzed the incidence of ARF and the risk factors for postoperative ARF. We used data from six medical centers to compare the performance of four machine learning models and performed internal validation to identify AAS patients who developed postoperative ARF. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to compare the performance of the predictive models. We compared the performance of the optimal machine learning prediction model with that of traditional prediction models. Data from three medical centers were used for external validation.

Results

The eXtreme Gradient Boosting (XGBoost) algorithm performed best in the internal validation process (AUC = 0.82), which was better than both the logistic regression (LR) prediction model (AUC = 0.77, p < 0.001) and the traditional scoring systems. Upon external validation, the XGBoost prediction model (AUC =0.81) also performed better than both the LR prediction model (AUC = 0.75, p = 0.03) and the traditional scoring systems. We created an online application based on the XGBoost prediction model.

Conclusions

We have developed a machine learning model that has better predictive performance than traditional LR prediction models as well as other existing risk scoring systems for postoperative ARF. This model can be utilized to provide early warnings when high-risk patients are found, enabling clinicians to take prompt measures.
Epidemiology and Risk Factors of Portal Venous System Thrombosis in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis
Authors: Lin Hanyang , Bai Zhaohui , Meng Fanjun , Wu Yanyan , Luo Li , Shukla Akash , Yoshida Eric M. , Guo Xiaozhong , Qi Xingshun
Published: January 2022

Background

Patients with inflammatory bowel disease (IBD) may be at risk of developing portal venous system thrombosis (PVST) with worse outcomes. This study aims to explore the prevalence, incidence, and risk factors of PVST among patients with IBD.

Methods

PubMed, Embase, and Cochrane Library databases were searched. All the eligible studies were divided according to the history of colorectal surgery. Only the prevalence of PVST in patients with IBD was pooled if the history of colorectal surgery was unclear. The incidence of PVST in patients with IBD after colorectal surgery was pooled if the history of colorectal surgery was clear. Prevalence, incidence, and risk factors of PVST were pooled by only a random-effects model. Subgroup analyses were performed in patients undergoing imaging examinations. Odds ratios (ORs) with 95% CIs were calculated.

Results

A total of 36 studies with 143,659 patients with IBD were included. Among the studies where the history of colorectal surgery was unclear, the prevalence of PVST was 0.99, 1.45, and 0.40% in ulcerative colitis (UC), Crohn's disease (CD), and unclassified IBD, respectively. Among the studies where all the patients underwent colorectal surgery, the incidence of PVST was 6.95, 2.55, and 3.95% in UC, CD, and unclassified IBD after colorectal surgery, respectively. Both the prevalence and incidence of PVST became higher in patients with IBD undergoing imaging examinations. Preoperative corticosteroids therapy (OR = 3.112, 95% CI: 1.017–9.525; p = 0.047) and urgent surgery (OR = 1.799, 95% CI: 1.079–2.998; p = 0.024) are significant risk factors of PVST in patients with IBD after colorectal surgery. The mortality of patients with IBD with PVST after colorectal surgery was 4.31% (34/789).

Conclusion

PVST is not rare, but potentially lethal in patients with IBD after colorectal surgery. More severe IBD, indicated by preoperative corticosteroids and urgent surgery, is associated with a higher risk of PVST after colorectal surgery. Therefore, screening for PVST by imaging examinations and antithrombotic prophylaxis in high-risk patients should be actively considered.

Systematic Review Registration

Registered on PROSPERO, Identifier: CRD42020159579.
Case Report: Self-Resolved Macular Edema Secondary to Congenital Retinal Macrovessels
Authors: Zheng Fang , Lai Kairan , Yin Houfa , He Jingliang , Xu Yufeng , Ye Panpan
Published: January 2022

Purpose

To report a case of macular edema secondary to congenital retinal macrovessels (CRMs), which resolved spontaneously without any treatment.

Observations

A 39-year-old female presented with blurry vision of the right eye for one day. Fundus examination revealed a branch of artery and vein of the inferior retinal arcade crossing the horizontal raphe. Optical coherence tomography (OCT) through the fovea showed cystoid macular edema in the outer plexiform layer. However, no leakage of the vessels was noticed by fundus fluorescein angiography (FFA). Observation was recommended with close follow-up. Two weeks later, the patient returned with good visual acuity, and the macular edema was resolved spontaneously.

Conclusions

Macular edema is a possible complication of CRM by increasing retinal capillary hydrostatic pressure. Treatment is not necessary for this kind of macular edema if no leakage of the vessels is noticed on FFA.
Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study
Authors: Dechamps Mélanie , De Poortere Julien , Martin Manon , Gatto Laurent , Daumerie Aurélie , Bouzin Caroline , Octave Marie , Ginion Audrey , Robaux Valentine , Pirotton Laurence , Bodart Julie , Gerard Ludovic , Montiel Virginie , Campion Alessandro , Gruson Damien , Van Dievoet Marie-Astrid , Douxfils Jonathan , Haguet Hélène , Morimont Laure , Derive Marc , Jolly Lucie , Bertrand Luc , Dumoutier Laure , Castanares-Zapatero Diego , Laterre Pierre-François , Horman Sandrine , Beauloye Christophe
Published: January 2022

Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1β and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.
Prediction and Clinically Important Factors of Acute Kidney Injury Non-recovery
Authors: Liu Chien-Liang , Tain You-Lin , Lin Yun-Chun , Hsu Chien-Ning
Published: January 2022

Objective

This study aimed to identify phenotypic clinical features associated with acute kidney injury (AKI) to predict non-recovery from AKI at hospital discharge using electronic health record data.

Methods

Data for hospitalized patients in the AKI Recovery Evaluation Study were derived from a large healthcare delivery system in Taiwan between January 2011 and December 2017. Living patients with AKI non-recovery were used to derive and validate multiple predictive models. In total, 64 candidates variables, such as demographic characteristics, comorbidities, healthcare services utilization, laboratory values, and nephrotoxic medication use, were measured within 1 year before the index admission and during hospitalization for AKI.

Results

Among the top 20 important features in the predictive model, 8 features had a positive effect on AKI non-recovery prediction: AKI during hospitalization, serum creatinine (SCr) level at admission, receipt of dialysis during hospitalization, baseline comorbidity of cancer, AKI at admission, baseline lymphocyte count, baseline potassium, and low-density lipoprotein cholesterol levels. The predicted AKI non-recovery risk model using the eXtreme Gradient Boosting (XGBoost) algorithm achieved an area under the receiver operating characteristic (AUROC) curve statistic of 0.807, discrimination with a sensitivity of 0.724, and a specificity of 0.738 in the temporal validation cohort.

Conclusion

The machine learning model approach can accurately predict AKI non-recovery using routinely collected health data in clinical practice. These results suggest that multifactorial risk factors are involved in AKI non-recovery, requiring patient-centered risk assessments and promotion of post-discharge AKI care to prevent AKI complications.
Safety and Efficacy of Tenofovir Alafenamide Fumarate in Early-Middle Pregnancy for Mothers With Chronic Hepatitis B
Authors: Chen Ruochan , Zou Ju , Long Liyuan , Huang Haiyue , Zhang Min , Fan Xuegong , Huang Yan
Published: January 2022

Background

Tenofovir alafenamide fumarate has been used in late pregnancy; however, no data exist regarding its safety and effectiveness in early and middle pregnancy for mothers with hepatitis B virus infection.

Aims

To design a prospective study to investigate the efficacy and safety of TAF in pregnant women with chronic HBV infection during early-middle pregnancy.

Methods

Pregnant women with active chronic hepatitis B who received tenofovir alafenamide fumarate during early and middle pregnancy were enrolled and followed up until 6 months postpartum. Infants received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoints were maternal hepatitis B virus DNA reduction at delivery and mother-to-child transmission rate.

Results

Among 98 mothers enrolled, 31 initiated tenofovir alafenamide fumarate in early pregnancy, and 57 in middle pregnancy. The mean (± standard deviation) age was 29.00 (±3.81) years. At delivery, 100% (98/98) of the mothers achieved hepatitis B virus DNA levels <200,000 IU/L. Ninety-eight infants were born, and none had congenital defects or malformations. All infants received hepatitis B virus immunoprophylaxis. The mother-to-child transmission rate was 0%. Growth parameters including body weight, height, and head circumference were comparable to the national standards for physical development. No severe adverse effects were reported in either mothers or infants. No severe liver function damage occurred in any of the mothers.

Conclusions

Initiating tenofovir alafenamide fumarate in early and middle pregnancy appears safe for both mothers and infants, and it is effective for controlling maternal disease as well as interrupting mother-to-child transmission.
Imatinib, a New Adjuvant Medical Treatment for Multifocal Villonodular Synovitis Associated to Noonan Syndrome: A Case Report and Literature Review
Authors: Dalla-Torre Romain , Crenn Vincent , Menu Pierre , Isidor Bertrand , Guillot Pascale , Le Goff Benoit , Geffroy Loic , Dauty Marc , Fouasson-Chailloux Alban
Published: January 2022

Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of the Rat Sarcoma/Mitogen-activated protein kinase (RAS/MAPK) pathway and characterized by short stature, heart defects, pectus excavatum, webbed neck, learning disabilities, cryptorchidism, and facial dysmorphia. Villonodular synovitis is a joint disorder most common in young adults characterized by an abnormal proliferation of the synovial membrane. Multifocal Villonodular synovitis is a rare disease whose recurrent nature can make its management particularly difficult. Currently, there is no systemic therapy recommended in diffuse and recurrent forms, especially because of the fear of long-term side effects in patients, who are usually young. Yet, tyrosine kinase inhibitors seem promising to reduce the effects of an aberrant colony stimulating factor-1 (CSF-1) production at the origin of the synovial nodule proliferation. We present here the case of a 21-year-old woman with NS associated to diffuse multifocal villonodular synovitis (DMVS). Our clinical case provides therapeutic experience in this very rare association. Indeed, in association with surgery, the patient improved considerably: she had complete daily life autonomy, knee joint amplitudes of 100° in flexion and 0° in extension and was able to walk for 10 min without any technical assistance. To our knowledge, this is the first case of a patient suffering from DMVS associated with a Noonan syndrome treated with Glivec®(oral administration at a dosage of 340 mg/m2in children, until disease regression) on a long-term basis.
Case Report: Associated Ocular Adverse Reactions With Inactivated COVID-19 Vaccine in China
Authors: Pang Kunpeng , Pan Lijie , Guo Hui , Wu Xinyi
Published: January 2022

The vaccine is still the best clinical measure for effective prevention and control of coronavirus disease 2019 (COVID-19). The vaccine-associated ocular adverse reactions should be noted in detail among the medical community. We reported twelve eyes of 9 patients presented at the Department of Ophthalmology, Qilu Hospital of Shandong University from March to August 2021 with ocular complaints following COVID-19 vaccination. The main inclusion criterion was the development of ocular symptoms within 14 days after receiving a dose of an inactivated COVID-19 vaccine. The mean (SD) age was 44.7 ± 16.5 years (range, 19–78 years), among which seven (77.8%) cases were women. The mean time of ocular adverse events was 7.1 days (range, 1–14 days) after receiving the inactivated COVID-19 vaccine. One patient was diagnosed with choroiditis, 1 with uveitis, 4 with keratitis, 1 with scleritis, 1 with acute retinal necrosis, and 1 with iridocyclitis. Although the causal relationship between vaccines and ocular adverse events cannot be established from this case series report, physicians should pay attention to the ocular adverse reactions following the COVID-19 vaccine administration.
Isolation of a Dissimilatory Iodate-Reducing Aromatoleum sp. From a Freshwater Creek in the San Francisco Bay Area
Authors: Reyes-Umana Victor , Kretschmer Jessica , Coates John D.
Published: January 2022

Recent reports of dissimilatory iodate-reducing microorganisms (DIRM) have arisen from studies of bacteria in marine environments. These studies described the physiology and distribution of DIRM while also demonstrating their presence in iodine-rich marine environments. We posited that despite lower iodine concentrations, terrestrial and freshwater ecosystems should also harbor DIRM. We established numerous enrichments from coastal and freshwater environments that actively remove amended iodate. We describe the physiology and genome of a new DIRM isolate, Aromatoleum toluclasticum sp. TC-10, emerging from a freshwater creek microcosm. Like other DIRM, A. toluclasticum sp. TC-10 couples acetate oxidation to iodate reduction with a concomitant increase in the OD600. Our results indicate that A. toluclasticum sp. TC-10 performs dissimilatory iodate reduction (DIR) using the recently described iodate reductase (Idr). We provide further evidence of horizontal gene transfer of the idr genes by demonstrating the lack of Idr in the closely related (99.93% 16S rDNA sequence identity) A. toluclasticum sp. MF63 and describe the heterogeneity of the accessory proteins associated with the iodate reduction island (IRI). These observations provide additional evidence that DIR is a horizontally acquired metabolism with broad environmental distribution beyond exclusively marine environments.
Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents
Authors: Hassan Entesar A. , Shehadi Ihsan A. , Elmaghraby Awatef M. , Mostafa Hadir M. , Zayed Salem E. , Abdelmonsef Aboubakr H.
Published: January 2022

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one(1)and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione(2)was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol(3, 4), 3,4-dihydroquinoline(7, 8)and thiopyran(10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9)was found to have the minimum binding energy (−11.5 and −8.5 Kcal/mol) as compared to the standard drug ampicillin (−8.0 and −8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities againstCandida albicansandAspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid(9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.
IGF2BP2 Regulates MALAT1 by Serving as an N6-Methyladenosine Reader to Promote NSCLC Proliferation
Authors: Han Le , Lei Guangyan , Chen Zhenghong , Zhang Yili , Huang Chen , Chen Wenjuan
Published: January 2022

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is an important posttranscriptional regulatory for stability and m6A modification. Here, we investigated the role of IGF2BP2 in non–small-cell lung cancer (NSCLC) proliferation. TCGA database was used to predict the expression and clinical significance of IGF2BP2 in normal and NSCLC samples. The expression of IGF2BP2 was further validated in NSCLC samples from surgery. Then we performed the functional study in NSCLC cell lines through overexpressing and knocking down IGF2BP2 in NSCLC cell lines in vitro and in vivo. The mechanism of interaction between IGF2BP2 and lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in NSCLC proliferation was determined by RIP assay. We demonstrated that IGF2BP2 is highly expressed in NSCLC and positively associated with poor overall survival (OS) and disease-free survival (DFS). We identified that lncRNA MALAT1 is a target of IGF2BP2 in NSCLC. IGF2BP2 promotes MALAT1 stability in an m6A-dependent mechanism, thus promoting its downstream target autophagy-related (ATG)12 expression and NSCLC proliferation.
Modeling Tumor Disease and Sepsis by Networks of Adaptively Coupled Phase Oscillators
Authors: Sawicki Jakub , Berner Rico , Löser Thomas , Schöll Eckehard
Published: January 2022

In this study, we provide a dynamical systems perspective to the modelling of pathological states induced by tumors or infection. A unified disease model is established using the innate immune system as the reference point. We propose a two-layer network model for carcinogenesis and sepsis based upon the interaction of parenchymal cells and immune cells via cytokines, and the co-evolutionary dynamics of parenchymal, immune cells, and cytokines. Our aim is to show that the complex cellular cooperation between parenchyma and stroma (immune layer) in the physiological and pathological case can be qualitatively and functionally described by a simple paradigmatic model of phase oscillators. By this, we explain carcinogenesis, tumor progression, and sepsis by destabilization of the healthy homeostatic state (frequency synchronized), and emergence of a pathological state (desynchronized or multifrequency cluster). The coupled dynamics of parenchymal cells (metabolism) and nonspecific immune cells (reaction of innate immune system) are represented by nodes of a duplex layer. The cytokine interaction is modeled by adaptive coupling weights between the nodes representing the immune cells (with fast adaptation time scale) and the parenchymal cells (slow adaptation time scale) and between the pairs of parenchymal and immune cells in the duplex network (fixed bidirectional coupling). Thereby, carcinogenesis, organ dysfunction in sepsis, and recurrence risk can be described in a correct functional context.
Atrial Fibrillation Is Not an Independent Determinant of Mortality Among Critically Ill Acute Ischemic Stroke Patients: A Propensity Score-Matched Analysis From the MIMIC-IV Database
Authors: Wu Chen-Shu , Chen Po-Huang , Chang Shu-Hao , Lee Cho-Hao , Yang Li-Yu , Chen Yen-Chung , Jhou Hong-Jie
Published: January 2022

Background/Objective

This study was conducted to investigate the clinical characteristics and outcomes of patients with acute ischemic stroke and atrial fibrillation (AF) in intensive care units (ICUs).

Methods

In the Medical Information Mart for Intensive Care IV database, 1,662 patients with acute ischemic stroke were identified from 2008 to 2019. Of the 1,662 patients, 653 had AF. The clinical characteristics and outcomes of patients with and without AF were compared using propensity score matching (PSM). Furthermore, univariate and multivariate Cox regression analyzes were performed.

Results

Of the 1,662 patients, 39.2% had AF. The prevalence of AF in these patients increased in a stepwise manner with advanced age. Patients with AF were older and had higher Charlson Comorbidity Index, CHA2DS2-VASc Score, HAS-BLED score, and Acute Physiology Score III than those without AF. After PSM, 1,152 patients remained, comprising 576 matched pairs in both groups. In multivariate analysis, AF was not associated with higher ICU mortality [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.64–1.42] or in-hospital mortality (HR, 1.08; 95% CI, 0.79–1.47). In Kaplan–Meier analysis, no difference in ICU or in-hospital mortality was observed between patients with and without AF.

Conclusions

AF could be associated with poor clinical characteristics and outcomes; however, it does not remain an independent short-term predictor of ICU and in-hospital mortality among patients with acute ischemic stroke after PSM with multivariate analysis.
Mast Syndrome Outside the Amish Community: SPG21 in Europe
Authors: Amprosi Matthias , Indelicato Elisabetta , Nachbauer Wolfgang , Hussl Anna , Stendel Claudia , Eigentler Andreas , Gallenmüller Constanze , Boesch Sylvia , Klopstock Thomas
Published: January 2022

Background:

Mast syndrome is a rare disorder belonging to the group of hereditary spastic paraplegias (HSPs). It is caused by bi-allelic mutations in the ACP33 gene, and is originally described in Old Order Amish. Outside this population, only one Japanese and one Italian family have been reported. Herein, we describe five subjects from the first three SPG21 families of German and Austrian descent.

Methods:

Five subjects with complicated HSP were referred to our centers. The workup consisted of neurological examination, neurophysiological and neuropsychological assessments, MRI, and genetic testing.

Results:

Onset varied from child- to adulthood. All patients exhibited predominant spastic para- or tetraparesis with positive pyramidal signs, pronounced cognitive impairment, ataxia, and extrapyramidal signs. Neurophysiological workup showed abnormal motor and sensory evoked potentials in all the patients. Sensorimotor axonal neuropathy was present in one patient. Imaging exhibited thin corpus callosum and global brain atrophy. Genetic testing revealed one heterozygous compound and two homozygous mutations in the ACP33 gene.

Conclusion:

Herein, we report the first three Austrian and two German patients with SPG21, presenting a detailed description of their clinical phenotype and disease course. Our report adds to the knowledge of this extremely rare disorder, and highlights that SPG21 must also be considered in the differential diagnosis of complicated HSP outside the Amish community.
Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats
Authors: Green Tabitha R. F. , Murphy Sean M. , Ortiz J. Bryce , Rowe Rachel K.
Published: January 2022

Few translational studies have examined how age-at-injury affects the glial response to traumatic brain injury (TBI). We hypothesized that rats injured at post-natal day (PND) 17 would exhibit a greater glial response, that would persist into early adulthood, compared to rats injured at PND35. PND17 and PND35 rats (n= 75) received a mild to moderate midline fluid percussion injury or sham surgery. In three cortical regions [peri-injury, primary somatosensory barrel field (S1BF), perirhinal], we investigated the glial response relative to age-at-injury (PND17 or PND35), time post-injury (2 hours, 1 day, 7 days, 25 days, or 43 days), and post-natal age, such that rats injured at PND17 or PND35 were compared at the same post-natal-age (e.g., PND17 + 25D post-injury = PND42; PND35 + 7D post-injury = PND42). We measured Iba1 positive microglia cells (area, perimeter) and quantified their activation status using skeletal analysis (branch length/cell, mean processes/cell, cell abundance). GFAP expression was examined using immunohistochemistry and pixel analysis. Data were analyzed using Bayesian multivariate multi-level models. Independent of age-at-injury, TBI activated microglia (shorter branches, fewer processes) in the S1BF and perirhinal cortex with more microglia in all regions compared to uninjured shams. TBI-induced microglial activation (shorter branches) was sustained in the S1BF into early adulthood (PND60). Overall, PND17 injured rats had more microglial activation in the perirhinal cortex than PND35 injured rats. Activation was not confounded by age-dependent cell size changes, and microglial cell body sizes were similar between PND17 and PND35 rats. There were no differences in astrocyte GFAP expression. Increased microglial activation in PND17 brain-injured rats suggests that TBI upregulates the glial response at discrete stages of development. Age-at-injury and aging with an injury are translationally important because experiencing a TBI at an early age may trigger an exaggerated glial response.