bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID term: a bilingual terminology for COVID-19
Authors: Ma Hetong , Shen Liu , Sun Haixia , Xu Zidu , Hou Li , Wu Sizhu , Fang An , Li Jiao , Qian Qing
Published: August 2021

Background

The coronavirus disease (COVID-19), a pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown its destructiveness with more than one million confirmed cases and dozens of thousands of death, which is highly contagious and still spreading globally. World-wide studies have been conducted aiming to understand the COVID-19 mechanism, transmission, clinical features, etc. A cross-language terminology of COVID-19 is essential for improving knowledge sharing and scientific discovery dissemination.

Methods

We developed a bilingual terminology of COVID-19 named COVID Term with mapping Chinese and English terms. The terminology was constructed as follows: (1) Classification schema design; (2) Concept representation model building; (3) Term source selection and term extraction; (4) Hierarchical structure construction; (5) Quality control (6) Web service. We built open access for the terminology, providing search, browse, and download services.

Results

The proposed COVID Term include 10 categories: disease, anatomic site, clinical manifestation, demographic and socioeconomic characteristics, living organism, qualifiers, psychological assistance, medical equipment, instruments and materials, epidemic prevention and control, diagnosis and treatment technique respectively. In total, COVID Terms covered 464 concepts with 724 Chinese terms and 887 English terms. All terms are openly available online (COVID Term URL: http://covidterm.imicams.ac.cn).

Conclusions

COVID Term is a bilingual terminology focused on COVID-19, the epidemic pneumonia with a high risk of infection around the world. It will provide updated bilingual terms of the disease to help health providers and medical professionals retrieve and exchange information and knowledge in multiple languages. COVID Term was released in machine-readable formats (e.g., XML and JSON), which would contribute to the information retrieval, machine translation and advanced intelligent techniques application.
The trend in primary health care preference in China: a cohort study of 12,508 residents from 2012 to 2018
Authors: Wan Guangsheng , Wei Xiaolin , Yin Hui , Qian Zhiwang , Wang Tingting , Wang Lina
Published: August 2021

Background

Residents’ preference for primary health care (PHC) determined their utilization of PHC. This study aimed to assess the determinants of PHC service preference among the residents and the trend in PHC service preference over time in China.

Methods

We employed the nationally representative longitudinal data from 2012 to 2018 based on the China Family Panel Studies. The analysis framework was guided by the Andersen model of health service utilization. We included a total of 12,508 individuals who have been successfully followed up in the surveys of 2012, 2014, 2016, and 2018 without any missing data. Logistic regressions were performed to analyze potential predictors of PHC preference behavior.

Results

The results indicated that individuals’ socio-economic circumstances and their health status factors were statistically significant determinants of PHC preference. Notably, over time, the residents’ likelihood of choosing PHC service represented a decreasing trend. Compare to 2012, the likelihood of PHC service preference decreased by 18.6% (OR, 0.814; 95% CI, 0.764–0.867) in 2014, 30.0% (OR, 0.700; 95% CI, 0.657–0.745) in 2016, and 34.9% (OR, 0.651; 95% CI, 0.611–0.694) in 2018. The decrease was significantly associated with the changes in residents’ health status.

Conclusions

The residents’ likelihood of choosing PHC service represented a decreasing trend, which was contrary to the objective of China’s National Health Reform in 2009. We recommend that policymakers adjust the primary service items in PHC facilities and strengthen the coordination of service between PHC institutions and higher-level hospitals.
IL-1β augments TGF-β inducing epithelial-mesenchymal transition of epithelial cells and associates with poor pulmonary function improvement in neutrophilic asthmatics
Authors: Zhang Shengding , Fan Yu , Qin Lu , Fang Xiaoyu , Zhang Cong , Yue Junqing , Bai Wenxue , Wang Gang , Chen Zhihong , Renz Harld , Skevaki Chrysanthi , Liu Xiansheng , Xie Min
Published: August 2021

Background

Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA.

Methods

Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells.

Results

NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1compared to EA. For all asthmatics, sputum IL-1β mRNA was positively correlated with protein expression. Sputum IL-1β mRNA and protein levels were negatively correlated to FEV1improvement. After subgrouping, the correlation between IL-1β mRNA and FEV1improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1β augmenting TGF-β1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors.

Conclusions

IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways.

Trial registration:This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).
Sch-net: a deep learning architecture for automatic detection of schizophrenia
Authors: Fu Jia , Yang Sen , He Fei , He Ling , Li Yuanyuan , Zhang Jing , Xiong Xi
Published: August 2021

Background

Schizophrenia is a chronic and severe mental disease, which largely influences the daily life and work of patients. Clinically, schizophrenia with negative symptoms is usually misdiagnosed. The diagnosis is also dependent on the experience of clinicians. It is urgent to develop an objective and effective method to diagnose schizophrenia with negative symptoms. Recent studies had shown that impaired speech could be considered as an indicator to diagnose schizophrenia. The literature about schizophrenic speech detection was mainly based on feature engineering, in which effective feature extraction is difficult because of the variability of speech signals.

Methods

This work designs a novel Sch-net neural network based on a convolutional neural network, which is the first work for end-to-end schizophrenic speech detection using deep learning techniques. The Sch-net adds two components, skip connections and convolutional block attention module (CBAM), to the convolutional backbone architecture. The skip connections enrich the information used for the classification by emerging low- and high-level features. The CBAM highlights the effective features by giving learnable weights. The proposed Sch-net combines the advantages of the two components, which can avoid the procedure of manual feature extraction and selection.

Results

We validate our Sch-net through ablation experiments on a schizophrenic speech data set that contains 28 patients with schizophrenia and 28 healthy controls. The comparisons with the models based on feature engineering and deep neural networks are also conducted. The experimental results show that the Sch-net has a great performance on the schizophrenic speech detection task, which can achieve 97.68% accuracy on the schizophrenic speech data set. To further verify the generalization of our model, the Sch-net is tested on open access LANNA children speech database for specific language impairment detection. The results show that our model achieves 99.52% accuracy in classifying patients with SLI and healthy controls. Our code will be available athttps://github.com/Scu-sen/Sch-net.

Conclusions

Extensive experiments show that the proposed Sch-net can provide aided information for the diagnosis of schizophrenia and specific language impairment.
Virulence characterization and clonal analysis of uropathogenic Escherichia coli metallo-beta-lactamase-producing isolates
Authors: Zangane Matin Fatemeh , Rezatofighi Seyedeh Elham , Roayaei Ardakani Mohammad , Akhoond Mohammad Reza , Mahmoodi Fahimeh
Published: August 2021

Background

Uropathogenic Escherichia coli (UPEC) is a major cause of urinary tract infection (UTI); however, treatment of UTI has been challenging due to increased antimicrobial resistance (AMR). One of the most important types of AMR is carbapenem resistance (CR). CR bacteria are known as an important threat to global public health today. Class B metallo-beta-lactamases (MBLs) are one of the major factors for resistance against carbapenems. We aimed to investigate the characteristics of UPEC isolates producing MBL.

Methods

A cross-sectional study was conducted from October 2018 to December 2019 in Ahvaz; Iran. UPEC isolates were identified by biochemical and molecular methods. Metallo-beta-lactamase-producing isolates were detected using modified carbapenem inactivation method (mCIM) and EDTA-CIM (eCIM) tests. MBL genes, phylogenetic group, and virulence genes profile of carbapenem resistant isolates were determined. Conjugation assay and plasmid profiling were conducted to evaluate the ability of transferring of CR to other E. coli isolates. Clonal similarity of isolates were assessed using Enterobacterial intergenic repetitive element sequence (ERIC)-PCR.

Results

Among 406 UPEC isolates, 12 (2.95%) carbapenem-resistant were detected of which 11 were phenotypically MBL-producing strains. Four isolates were resistant to all investigated antimicrobial agents and were considered possible pandrug-resistant (PDR). blaNDM, blaOXA-48, blaIMP-1, and blaIMP-2 genes were found in 9, 5, 1, and 1 isolates, respectively. Among 30 virulence genes investigated, the traT, fyuA followed by fimH, and iutA with the frequency of 8 (66.7%), 8 (66.7%), 7 (58.3%), and 7 (58.3%) were the most identified genes, respectively. Siderophore production was the main virulence trait among carbapenem-resistant UPEC isolates. Except for two, all other isolates showed weak to moderate virulence index. In all recovered isolates, CR was readily transmitted via plasmids to other isolates during conjugation experiments.

Conclusion

MBL and carbapenemase genes, especially blaNDM and blaOXA-48 are spreading rapidly among bacteria, which can be a threat to global public health. Therefore monitoring the emergence and dissemination of new AMR is necessary to continuously refine guidelines for empiric antimicrobial therapy. Understanding the mechanisms of resistance and virulence in this group of bacteria can play an effective role in providing new therapeutic methods.
BPA and BPS affect the expression of anti-Mullerian hormone (AMH) and its receptor during bovine oocyte maturation and early embryo development
Authors: Saleh Angela Christina , Sabry Reem , Mastromonaco Gabriela Fabiana , Favetta Laura Alessandra
Published: August 2021

Background

Exposure to endocrine-disrupting chemicals, such as Bisphenol A (BPA) and Bisphenol S (BPS), is widespread and has negative implications on embryonic development. Preliminary evidence revealed that in women undergoing IVF treatment, urinary BPA levels were associated with low serum anti-Mullerian hormone, however a definitive relationship between the two has not yet been characterized.

Methods

This study aimed to evaluate BPA and BPS effects on in vitro oocyte maturation and early preimplantation embryo development through i) analysis of anti-Mullerian hormone (AMH) and anti-Mullerian hormone receptor II (AMHRII), ii) investigation of developmental parameters, such as cleavage, blastocyst rates and developmental arrest, iii) detection of apoptosis and iv) assessment of possible sex ratio skew. An in vitro bovine model was used as a translational model for human early embryonic development. We first assessed AMH and AMHRII levels after bisphenol exposure during oocyte maturation. Zygotes were also analyzed during cleavage and blastocysts stages. Techniques used include in vitro fertilization, quantitative polymerase chain reaction (qPCR), western blotting, TUNEL and immunofluorescence.

Results

Our findings show that BPA significantly decreased cleavage (p < 0.001), blastocyst (p < 0.005) and overall developmental rates as well as significantly increased embryonic arrest at the 2–4 cell stage (p < 0.05). Additionally, both BPA and BPS significantly increased DNA fragmentation in 2–4 cells, 8–16 cells and blastocyst embryos (p < 0.05). Furthermore, BPA and BPS alter AMH and AMHRII at the mRNA and protein level in both oocytes and blastocysts. BPA, but not BPS, also significantly skews sex ratios towards female blastocysts (p < 0.05).

Conclusion

This study shows that BPA affects AMH and AMHRII expression during oocyte maturation and that BPS exerts its effects to a greater extent after fertilization and therefore may not be a safer alternative to BPA. Our data lay the foundation for future functional studies, such as receptor kinetics, downstream effectors, and promoter activation/inhibition to prove a functional relationship between bisphenols and the AMH signalling system.
Clinical outcome of renal cancer patients who early interrupted immunotherapy due to serious immune-related adverse events. Meet-Uro 13 trial on behalf of the MeetUro investigators
Authors: Stellato Marco , Procopio Giuseppe , De Giorgi Ugo , Maruzzo Marco , Bimbatti Davide , Mennitto Alessia , Sbrana Andrea , Roviello Giandomenico , Casadei Chiara , Sepe Pierangela , Pignata Sandro , Santini Daniele
Published: August 2021

Background

Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, 2020); Haanen (Ann Oncol 28:119–142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs.

Methods

We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group.

Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago).

Results

18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0).

Conclusions

ICIs seem to maintain efficacy even after early interruption due to severe irAE.
Targeted provider education and pre-visit planning increase rates of formal depression screening in childhood-onset SLE
Authors: Mulvihill Evan , Furru Rebecca , Goldstein-Leever Alana , Driest Kyla , Lemle Stephanie , MacDonald Darby , Frost Emily , Sivaraman Vidya
Published: August 2021

Background

Despite being at high risk for depression, patients with childhood-onset systemic lupus erythematosus (c-SLE) are infrequently and inconsistently screened for depression by their pediatric rheumatologists. We aimed to systematically increase rates of formal depression screening for c-SLE patients in an academic Pediatric Rheumatology clinic.

Methods

Our multi-disciplinary quality improvement (QI) team used electronic health record (EHR) documentation to retroactively calculate baseline rates of documented depression screening using the Patient Health Questionnaire-9 (PHQ-9). We then engaged key stakeholders to develop a clinical workflow for formal depression screening in the clinic. We also provided education to providers regarding mental health disorders in c-SLE, with an emphasis on prevalence, screening methods, and management of positive screens. We then used the Plan-Do-Study Act (PDSA) method of QI to systematically evaluate and adjust our process in real time. The primary outcome was the percentage of patients with c-SLE seen per month who had a documented PHQ-9 screening within the past year.

Results

The percentage of children with documented PHQ-9 results ranged from 0 to 4.5 % at baseline to 91.0 % within 12 months of project initiation. By the end of the project, monthly screening rates greater than 80 % has been sustained for 10 months. As a result of these efforts, twenty-seven (48.2 %) patients with at least mild depressive symptoms were identified while seven (12.5 %) with thoughts of self-harm were referred to appropriate mental health resources.

Conclusions

Routine formal depression screening is feasible in a busy subspecialty clinic. Using QI methods, rates of formal depression screening among children with c-SLE were increased from an average of 3.3 % per month to a sustained monthly rate of greater than 80 %. Individuals with depressive symptoms and/or thoughts of self-harm were identified and referred to appropriate mental health resources.
Cannons and sparrows II: the enhanced Bernoulli exact method for determining statistical significance and effect size in the meta-analysis of k 2 × 2 tables
Authors: Paul Lawrence M.
Published: August 2021

Background

The use of meta-analysis to aggregate the results of multiple studies has increased dramatically over the last 40 years. For homogeneous meta-analysis, the Mantel–Haenszel technique has typically been utilized. In such meta-analyses, the effect size across the contributing studies of the meta-analysis differs only by statistical error. If homogeneity cannot be assumed or established, the most popular technique developed to date is the inverse-variance DerSimonian and Laird (DL) technique (DerSimonian and Laird, in Control Clin Trials 7(3):177–88, 1986). However, both of these techniques are based on large sample, asymptotic assumptions. At best, they are approximations especially when the number of cases observed in any cell of the corresponding contingency tables is small.

Results

This research develops an exact, non-parametric test for evaluating statistical significance and a related method for estimating effect size in the meta-analysis of k 2 × 2 tables for any level of heterogeneity as an alternative to the asymptotic techniques. Monte Carlo simulations show that even for large values of heterogeneity, the Enhanced Bernoulli Technique (EBT) is far superior at maintaining the pre-specified level of Type I Error than the DL technique. A fully tested implementation in the R statistical language is freely available from the author. In addition, a second related exact test for estimating the Effect Size was developed and is also freely available.

Conclusions

This research has developed two exact tests for the meta-analysis of dichotomous, categorical data. The EBT technique was strongly superior to the DL technique in maintaining a pre-specified level of Type I Error even at extremely high levels of heterogeneity. As shown, the DL technique demonstrated many large violations of this level. Given the various biases towards finding statistical significance prevalent in epidemiology today, a strong focus on maintaining a pre-specified level of Type I Error would seem critical. In addition, a related exact method for estimating the Effect Size was developed.
Similarities and differences in the localization, trafficking, and function of P-glycoprotein in MDR1-EGFP-transduced rat versus human brain capillary endothelial cell lines
Authors: Gericke Birthe , Borsdorf Saskia , Wienböker Inka , Noack Andreas , Noack Sandra , Löscher Wolfgang
Published: August 2021

Background

In vitro models based on brain capillary endothelial cells (BCECs) are among the most versatile tools in blood–brain barrier research for testing drug penetration into the brain and how this is affected by efflux transporters such as P-glycoprotein (Pgp). However, compared to freshly isolated brain capillaries or primary BCECs, the expression of Pgp in immortalized BCEC lines is markedly lower, which prompted us previously to transduce the widely used human BCEC line hCMEC/D3 with a doxycycline-inducibleMDR1-EGFP fusion plasmid. The EGFP-labeled Pgp in these cells allows studying the localization and trafficking of the transporter and how these processes are affected by drug exposure. Here we used this strategy for the rat BCEC line RBE4 and performed a face-to-face comparison of RBE4 and hCMEC/D3 wild-type (WT) andMDR1-EGFP transduced cells.

Methods

MDR1-EGFP-transduced variants were derived from WT cells by lentiviral transduction, using anMDR1-linker-EGFP vector. Localization, trafficking, and function of Pgp were compared in WT andMDR1-EGFP transduced cell lines. Primary cultures of rat BCECs and freshly isolated rat brain capillaries were used for comparison.

Results

All cells exhibited typical BCEC morphology. However, significant differences were observed in the localization of Pgp in that RBE4-MDR1-EGFP cells expressed Pgp primarily at the plasma membrane, whereas in hCMEC/D3 cells, the Pgp-EGFP fusion protein was visible both at the plasma membrane and in endolysosomal vesicles. Exposure to doxorubicin increased the number of Pgp-EGFP-positive endolysosomes, indicating a lysosomotropic effect. Furthermore, lysosomal trapping of doxorubicin was observed, likely contributing to the protection of the cell nucleus from damage. In cocultures of WT andMDR1-EGFP transduced cells, intercellular Pgp-EGFP trafficking was observed in RBE4 cells as previously reported for hCMEC/D3 cells. Compared to WT cells, theMDR1-EGFP transduced cells exhibited a significantly higher expression and function of Pgp. However, the junctional tightness of WT andMDR1-EGFP transduced RBE4 and hCMEC/D3 cells was markedly lower than that of primary BCECs, excluding the use of the cell lines for studying vectorial drug transport.

Conclusions

The present data indicate thatMDR1-EGFP transduced RBE4 cells are an interesting tool to study the biogenesis of lysosomes and Pgp-mediated lysosomal drug trapping in response to chemotherapeutic agents and other compounds at the level of the blood–brain barrier.
Trans-apical aortic valve implantation for quadricuspid aortic valve with aortic regurgitation using J-valve system: a case reports
Authors: Luo Chaodi , Jiang Yi , Chen Qiang , Yan Yang , Han Dan
Published: August 2021

Background

Quadricuspid aortic valve (QAV) is a rare congenital heart defect usually accompanied with different hemodynamic abnormalities. Due to the rarity of QAV, treatment and prognosis of QAV patients with aortic regurgitation still remain challenging. We here present the first case of a patient with severe QAV regurgitation who underwent successful treatment and performed favorable prognosis with transapical aortic valve implantation (TAVI) using J-Valve system.

Case presentation

A 62-year-old man experienced intermittent palpitation, shortness of breath and chest pain. Echocardiography revealed congenital QAV with massive aortic regurgitation and mild aortic stenosis, left ventricular enlargement. Aortic valve replacement was successfully performed with TAVI using J-Valve system. The postoperation and follow-up was uneventful.

Conclusion

TAVI using J-Valve system has emerged as a new high success rate method for treatment of patients with simple non-calcified aortic valve insufficiency.
A population-based study to estimate survival and standardized mortality of tuberous sclerosis complex (TSC) in Taiwan
Authors: Peng Jui-Hui , Tu Hung-Pin , Hong Chien-Hui
Published: August 2021

Background

Tuberous sclerosis complex (TSC) is an autosomal dominant disease with systemic manifestations, which can cause significant mortality and morbidity. Population-based epidemiological studies on TSC mortality and survival remain scarce, though several recent studies provide evidence that TSC survival rates are high and disease prognosis is fair for most patients. This study aims to estimate the life expectancy and mortality statistics in Taiwanese TSC patients, investigate prognosis and associations of TSC mortality based on demographic variables, and compare these results to past literature, especially for Asian patients.

Methods

Taiwanese National Health Insurance (NHI) insurees can obtain Catastrophic Illness Certificates (CIC) for certain eligible diseases to waive copayments after diagnosis by two independent physicians. CIC holders for TSC during 1997–2010 were identified from the NHI Research Database. Queries on enrollment (CIC acquisition) age, endpoint (end of query period or death) age, sex, and comorbidities were obtained. Patients were separated into cohorts (endpoint age, sex, and age of diagnosis), and analyzed accordingly.

Results

471 patients (232 male, 239 female) were identified, of which 14 died. Compared to literature, patients showed similar demographics (age range, diagnosis age, sex distribution); similar manifestations and prevalence (epilepsy, intellectual disability, renal disease); lower disease prevalence (1 in 63,290); lower mortality (0.21% per year); and near-identical standardized mortality ratio (4.99). A cumulative mortality of 4.08% was found over 14 years, though mortality plateaued at 7 years post-enrollment, suggesting a good overall survival rate; comparable with previous studies in Asian patients. Enrollment age was a significant prognostic factor, with late-enrollment (age > 18) patients at higher risk for all-cause mortality (Hazard ratio = 6.54). Average remaining lifetime was significantly lower than the general population, and decreased with age.

Conclusions

This study reports a population-based disease database, highlights the importance of diagnosis age in prognosis prediction, and suggests the role of renal manifestations in mortality. Furthermore, it corroborates recent TSC studies in the Asian population in terms of survival. Overall, physician vigilance, early diagnosis, and careful monitoring are beneficial for disease outcome and patient survival.
Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration
Authors: Mohan Swetha , Sampognaro Paul J. , Argouarch Andrea R. , Maynard Jason C. , Welch Mackenzie , Patwardhan Anand , Courtney Emma C. , Zhang Jiasheng , Mason Amanda , Li Kathy H. , Huang Eric J. , Seeley William W. , Miller Bruce L. , Burlingame Alma , Jacobson Mathew P. , Kao Aimee W.
Published: August 2021

Background

Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints.

Results

In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease.

Conclusions

This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP-Pgrn. Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD-Pgrn and other progranulin-related diseases.
A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials
Authors: Hills N. K. , Lyimo J. , Nahid P. , Savic R. M. , Lienhardt C. , Phillips P. P. J.
Published: August 2021

Background

Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies

Methods

We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described.

Results

From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes.

Conclusions

In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal.

PROSPERO registration

PROSPERO CRD42020197993. Registration 11 August 2020.
Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis
Authors: Bai Jie , Li Lijun , Kou Ni , Bai Yuwen , Zhang Yaoyang , Lu Yun , Gao Lu , Wang Fu
Published: August 2021

Background

Bone tissue engineering is a new concept bringing hope for the repair of large bone defects, which remains a major clinical challenge. The formation of vascularized bone is key for bone tissue engineering. Growth of specialized blood vessels termed type H is associated with bone formation. In vivo and in vitro studies have shown that low level laser therapy (LLLT) promotes angiogenesis, fracture healing, and osteogenic differentiation of stem cells by increasing reactive oxygen species (ROS). However, whether LLLT can couple angiogenesis and osteogenesis, and the underlying mechanisms during bone formation, remains largely unknown.

Methods

Mouse bone marrow mesenchymal stem cells (BMSCs) combined with biphasic calcium phosphate (BCP) grafts were implanted into C57BL/6 mice to evaluate the effects of LLLT on the specialized vessel subtypes and bone regeneration in vivo. Furthermore, human BMSCs and human umbilical vein endothelial cells (HUVECs) were co-cultured in vitro. The effects of LLLT on cell proliferation, angiogenesis, and osteogenesis were assessed.

Results

LLLT promoted the formation of blood vessels, collagen fibers, and bone tissue and also increased CD31hiEMCNhi-expressing type H vessels in mBMSC/BCP grafts implanted in mice. LLLT significantly increased both osteogenesis and angiogenesis, as well as related gene expression (HIF-1α, VEGF, TGF-β) of grafts in vivo and of co-cultured BMSCs/HUVECs in vitro. An increase or decrease of ROS induced by H2O2or Vitamin C, respectively, resulted in an increase or decrease of HIF-1α, and a subsequent increase and decrease of VEGF and TGF-β in the co-culture system. The ROS accumulation induced by LLLT in the co-culture system was significantly decreased when HIF-1α was inhibited with DMBPA and was followed by decreased expression of VEGF and TGF-β.

Conclusions

LLLT enhanced vascularized bone regeneration by coupling angiogenesis and osteogenesis. ROS/HIF-1α was necessary for these effects of LLLT. LLLT triggered a ROS-dependent increase of HIF-1α, VEGF, and TGF-β and resulted in subsequent formation of type H vessels and osteogenic differentiation of mesenchymal stem cells. As ROS also was a target of HIF-1α, there may be a positive feedback loop between ROS and HIF-1α, which further amplified HIF-1α induction via the LLLT-mediated ROS increase. This study provided new insight into the effects of LLLT on vascularization and bone regeneration in bone tissue engineering.
The function of LncRNA-H19 in cardiac hypertrophy
Authors: Su Wenhua , Huo Qian , Wu Hao , Wang Lulin , Ding Xiaoxue , Liang Liwen , Zhou Liang , Zhao Yan , Dan Juhua , Zhang Hong
Published: August 2021

Cardiac hypertrophy, characterized by the enlargement of cardiomyocytes, is initially an adaptive response to physiological and pathological stimuli. Decompensated cardiac hypertrophy is related to fibrosis, inflammatory cytokine, maladaptive remodeling, and heart failure. Although pathological myocardial hypertrophy is the main cause of hypertrophy-related morbidity and mortality, our understanding of its mechanism is still poor. Long noncoding RNAs (lncRNAs) are noncoding RNAs that regulate various physiological and pathological processes through multiple molecular mechanisms. Recently, accumulating evidence has indicated that lncRNA-H19 is a potent regulator of the progression of cardiac hypertrophy. For the first time, this review summarizes the current studies about the role of lncRNA-H19 in cardiac hypertrophy, including its pathophysiological processes and underlying pathological mechanism, including calcium regulation, fibrosis, apoptosis, angiogenesis, inflammation, and methylation. The context within which lncRNA-H19 might be developed as a target for cardiac hypertrophy treatment is then discussed to gain better insight into the possible biological functions of lncRNA-H19 in cardiac hypertrophy.
On Green’s function of Cauchy–Dirichlet problem for hyperbolic equation in a quarter plane
Authors: Sadybekov Makhmud , Derbissaly Bauyrzhan
Published: August 2021

The definition of a Green’s function of a Cauchy–Dirichlet problem for the hyperbolic equation in a quarter plane is given. Its existence and uniqueness have been proven. Representation of the Green’s function is given. It is shown that the Green’s function can be represented by the Riemann–Green function.
Effect of deregulation of repressor-specific carbon catabolite repression on carbon source consumption in Escherichia coli
Authors: Seong Hyeon Jeong , Jang Yu-Sin
Published: August 2021

Escherichia coli has been used as a host to construct the cell factory for biobased production of chemicals from renewable feedstocks. Because galactose is found in marine biomass as a major component, the strategy for galactose utilization in E. coli has been gained more attention. Although galactose and glucose co-fermentation has been reported using the engineered E. coli strain, few reports have covered fermentation supplemented with galactose as a sole carbon source in the mutant lacking the repressor-specific carbon catabolite repression (CCR). Here, we report the effects of the deregulation of the repressor-specific CCR (galR− and galS−) in fermentation supplemented with galactose as a sole carbon source, using the engineered E. coli strains. In the fermentation using the galR− and galS− double mutant (GR2 strain), an increase of rates in sugar consumption and cell growth was observed compared to the parent strain. In the glucose fermentation, wild-type W3110 and its mutant GR2 and GR2PZ (galR−, galS−, pfkA−, and zwf−) consumed sugar at a higher rate than those values obtained from galactose fermentation. However, the GR2P strain (galR−, galS−, and pfkA−) showed no difference between fermentations using glucose and galactose as a sole carbon source. This study provides essential information for galactose fermentation using the CCR-deregulated E. coli strains.
Clinical study on the diagnosis of porcine streptococcal meningitis with negative blood and cerebrospinal fluid culture by next-generation sequencing
Authors: Zhao Eryi , Wang Daimei , Li Na , Huang Shixiong , Zhao Zhongyan , Hu Shijun , He Xiangying , Wen Guoqiang
Published: August 2021

Background

Streptococcus suis (Ss) is a Gram-positive and anaerobic zoonotic pathogen that is susceptible to all populations and can cause meningitis, septicemia, endocarditis and arthritis in humans.

Methods

In this study, patients with meningitis who were admitted to our hospital with negative blood and cerebrospinal fluid culture were divided into a next-generation sequencing group and a control group. In the next-generation sequencing group, we used the next-generation sequencing method to detect pathogenic bacteria in the patients’ cerebrospinal fluid. In the control group, we used blood and cerebrospinal fluid bacterial culture method to detect pathogenic bacteria in the patients' cerebrospinal fluid. The detection rates of pathogenic bacteria in the cerebrospinal fluid of the two groups were compared and analyzed.

Results

A total of 18 patients were included in this study, including 8 patients in the next-generation sequencing group and 10 patients in the control group. The mean age (P = 0.613) and mean disease duration (P = 0.294) were similar in both groups. Patients in the next-generation sequencing group had a leukocyte count of 13.13 ± 4.79 × 109, a neutrophil percentage of 83.39 ± 10.36%, and a C-reactive protein level of 134.95 ± 107.69 mg/L. Patients in the control group had a temperature of 38.32 ± 1.07, a leukocyte count of 8.00 ± 2.99 × 109, and a neutrophil percentage of 74.61 ± 8.89%, and C-reactive protein level was 4.75 ± 6.8 mg/L. The statistical results showed that the leukocytes (P = 0.013) and C-reactive protein levels (P = 0.001) were significantly higher in the patients of the next-generation sequencing group than in the control group. No statistically significant differences were seen in body temperature and neutrophil percentage between the two groups (P > 0.05). The incidence of intracranial pressure and meningeal irritation signs were similar in the two groups (P > 0.05). The detection rate of Streptococcus suis in the cerebrospinal fluid of patients in the next-generation sequencing group was 100%, and the detection rate of Streptococcus suis in the cerebrospinal fluid of the control group was 0%.

Conclusion

The detection rate of Streptococcus suis infection in cerebrospinal fluid by next-generation sequencing was significantly higher than that by blood and cerebrospinal fluid bacterial culture. Therefore, the diagnosis of porcine streptococcal meningitis by next-generation sequencing method is worthy of clinical promotion and application.
Association between HLA genotypes and COVID-19 susceptibility, severity and progression: a comprehensive review of the literature
Authors: Migliorini Filippo , Torsiello Ernesto , Spiezia Filippo , Oliva Francesco , Tingart Markus , Maffulli Nicola
Published: August 2021

The COVID-19 pandemic has markedly impacted on cultural, political, and economic structures all over the world. Several aspects of its pathogenesis and related clinical consequences have not yet been elucidated. Infection rates, as well morbidity and mortality differed within countries. It is intriguing for scientists to understand how patient genetics may influence the outcome of the condition, to clarify which aspects could be related the clinical variability of SARS-CoV-2 disease. We reviewed the studies exploring the role of human leukocyte antigens (HLA) genotypes on individual responses to SARS-CoV-2 infection and/or progression, discussing also the contribution of the immunological patterns MHC-related. In March 2021, the main online databases were accessed. All the articles that investigated the possible association between the HLA genotypes and related polymorphisms with susceptibility, severity and progression of COVID-19 were considered. Although both genetic and environmental factors are certainly expected to influence the susceptibility to or protection of individuals, the HLA and related polymorphisms can influence susceptibility, progression and severity of SARS-CoV-2 infection. The crucial role played by HLA molecules in the immune response, especially through pathogen-derived peptide presentation, and the huge molecular variability of HLA alleles in the human populations could be responsible for the different rates of infection and the different patients following COVID-19 infection.
Lurasidone in the long-term treatment of Japanese patients with bipolar I disorder: a 52 week open label study
Authors: Higuchi Teruhiko , Kato Tadafumi , Miyajima Mari , Watabe Kei , Masuda Takahiro , Hagi Katsuhiko , Ishigooka Jun
Published: August 2021

Background

The current study evaluated the long-term (52 week) safety and impact on symptom measures of lurasidone (with or without lithium or valproate) for the treatment of bipolar I disorder in Japanese patients.

Methods

Bipolar patients for this open-label flexibly dosed lurasidone (20–120 mg/day) study were recruited from those with a recent/current depressive episode who completed an initial 6 week, double-blind, placebo-controlled, lurasidone study (depressed group), and those with a recent/current manic, hypomanic, or mixed episode (non-depressed group) who agreed to enroll directly into the long-term study. Measures of adverse events and safety included treatment-emergent adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Symptom measures included Montgomery Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS).

Results

The most common adverse events associated with lurasidone were akathisia (30.7%), nasopharyngitis (26.6%), nausea (12.1%), and somnolence (12.1%). Minimal changes in lipids and measures of glycemic control occurred. Mean change in body weight was + 1.0 kg in the non-depressed group and − 0.8 kg in the depressed group. MADRS total scores declined by a mean (SD) of 2.0 (14.7) points from long-term baseline to endpoint in the depressed group who had received placebo in the prior 6 week trial. The depressed group that had received lurasidone during the prior 6 week study maintained their depressive symptom improvements. For the non-depressed group, YMRS total scores decreased over time.

Limitations

No control group was included, treatment was open-label, and 49.7% of patients completed the 52 week study.

Conclusions

Long-term treatment with lurasidone 20–120 mg/day for Japanese patients with bipolar disorder maintained improvements in depressive symptoms for depressed patients who were treated in a prior 6 week trial and led to improvements in manic symptoms among a newly recruited subgroup of patients with a recent/current manic, hypomanic, or mixed episode. Few changes in weight or metabolic parameters were evident.

Clinical trial registration: JapicCTI-132319, clinicaltrials.gov—NCT01986114.
Conversion of lignocellulosic waste into effective flocculants: synthesis, characterization, and performance
Authors: Jahedi Elham , Panahi Reza
Published: August 2021

Development of cationic flocculants from lignocellulosic wastes not only eliminates the health and environmental concerns associated with the use of conventional chemicals, but also is the way of waste valorization. In the present study, cellulose fibers extracted from rice husk were cationized through an optimization method based on response surface methodology. The fibers cationized at the optimal conditions had a zeta-potential of 15.2 ± 1.0 mV, while the highest potential was + 8.76 mV, for the samples developed before optimization. FTIR analysis proved the presence of the corresponding functional groups. The functionalized fibers were biodegradable and had absolutely positive surface charges at a broad pH range. The cationized fibers were employed as a flocculant to remove turbidity from the synthetic wastewaters at various pHs and initial turbidities. The cationic fibers showed the excellent turbidity removals up to 98.5% from the synthetic wastewater without the need for conventional coagulants. In contrast to traditionally cationized fibers, the synthesized flocculants did not affect the effluent color during coagulation–flocculation. The charge neutralization and bridging through adsorption were the governing mechanisms of flocculation. The procedure can be applied on lignocellulosic wastes to develop cationic fibers with the excellent flocculation ability and suitable operational characteristics.