bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Integrin α10β1-Selected Mesenchymal Stem Cells Home To Cartilage Defects In The Rabbit Knee And Assume A Chondrocyte-Like Phenotype
Authors: Andersen Camilla , Uvebrant Kristina , Mori Yuki , Aarsvold Stacie , Jacobsen Stine , Berg Lise Charlotte , Lundgren-Åkerlund Evy , Lindegaard Casper
Published: March 2022

Background: Mesenchymal stem cells (MSCs) have shown promising results in stimulating cartilage repair and in the treatment of osteoarthritis (OA). However, the fate of the MSCs after intra-articular injection and their role in cartilage regeneration is not clear. To address these questions, this study investigated 1) homing of labeled human adipose tissue derived integrin α10β1-selected MSCs (integrin α10-MSCs), to a cartilage defect in a rabbit model and 2) the ability of the integrin a10-MSCs to differentiate to chondrocytes and to produce cartilage matrix molecules in vivo.Design: Integrin α10-MSCs were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) co-conjugated with Rhodamine-B to allow visualization by both MRI and fluorescence microscopy. A cartilage defect was created in the articular cartilage of the intertrochlear groove of the femur of rabbits. Seven days post-surgery, labeled integrin α10-MSCs or vehicle were injected into the joint. Migration and distribution of the SPION-labeled integrin α10-MSCs was evaluated by high field 9.4T MRI up to 10 days after injection. Tissue sections from the repair tissue in the defects were examined by fluorescence microscopy.Results: In vitro characterization of the labeled integrin α10-MSCs demonstrated maintained viability, proliferation rate and tri-lineage differentiation capacity compared to unlabeled MSCs. In vivo MRI analysis detected the labeled integrin α10-MSCs in the cartilage defects at all time points from 12 hours after injection until day 10 with a peak concentration between day 1-4 after injection. The labeled MSCs were also detected lining the synovial membrane at the early time points. Fluorescence analysis confirmed the presence of the labeled integrin α10-MSCs in all layers of the cartilage repair tissue and showed co-localization between the MSCs and the specific cartilage molecules aggrecan and collagen type II indicating in vivo differentiation of the MSCs to chondrocyte-like cells. No adverse effects of the α10-MSC treatment were detected during the study period.Conclusion: Our results demonstrated migration and homing of human integrin α10β1-selected MSCs to cartilage defects in the rabbit knee after intra-articular administration indicating that the MSCs have a direct role in the cartilage regeneration.
Positive Correlation Between [18F]-fluorodeoxyglucose (FDG) Uptake and Tumor-proliferating Antigen Ki-67 Expression in Adrenocortical Carcinomas
Authors: Libe Rossella , Pais Aurore , Vialon Florian , Guignat Laurence , Bonnet Fideline , Huillard Olivier , Assié Guillaume , Gaillard Martin , Dousset Bertrand , Gaujoux Sébastien , Barat Maxime , Dohan Anthony , Sibony Mathilde , Bertherat Jérôme , Cottereau Anne Segolene , Tenenbaum Florence , Coste Joël , Groussin Lionel
Published: March 2022

Purpose Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, whose diagnosis is suspected by conventional radiology and hormonal investigations. 18F-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) could help predict malignancy, but more consistent data are necessary to support future guidelines.MethodsA cohort of 63 patients with histologically proven ACC (n=55) or metastatic ACC with steroid oversecretion (n=8) was assembled. All patients underwent a [18F]-FDG PET and the maximum Standardized Uptake Value (SUVmax) and the adrenal-to-liver SUVmax ratio were calculated. The [18F]-FDG PET parameters were compared with clinical, pathological and outcome data.ResultsA positive correlation between [18F]-FDG PET parameters (SUVmax and adrenal-to-liver SUVmax ratio) and tumor size, ENSAT (European Network for the Study of Adrenal Tumors) staging, total Weiss score and the proliferation marker Ki67 was found. The strong correlation between SUVmax and Ki67 (r=0.47, p=0.0009) suggests a relationship between FDG uptake levels and tumor proliferation. Associations between outcome parameters (progression free or overall survival) and [18F]-FDG PET parameters were weaker. Fifty-six out of 63 patients (89%) had an adrenal-to-liver SUVmax >1.45, a previously defined cutoff value to predict malignancy. Seven ACC (11%) had a lower uptake, with a Ki67 expression level statistically lower compared to other ACC.ConclusionThis large cohort study shows that most ACC demonstrate high [18F]-FDG uptake. However, the positive correlation observed between SUVmax and Ki67 expression levels seems to explain the possibility of identifying some ACC with a low [18F]-FDG uptake and Ki67 ≤ 10%.
Cone-beam Computed Tomography is Not a Mandatory Procedure in Adrenal Venous Sampling for Primary Hyperaldosteronism
Authors: Cai Ran , Hu Chao , LI Hai-Yang
Published: March 2022

Objectives: To investigate the necessity of cone-beam computed tomography (CBCT) in adrenal venous sampling (AVS).Methods: This retrospective study included 120 consecutive patients with primary hyperaldosteronism who underwent AVS. Based on the learning curve of the interventional radiologists, the patients were divided into the learning (n=36) and proficiency (n=84) groups chronologically. Based on the imaging pattern of the right adrenal vein (RAV), the patients were divided into the typical (n=36) and atypical (n=84) groups. The success rate, radiation dose, and sampling time were compared among the entire study population and each subgroup.Results: A total of 69 patients underwent CBCT, whereas 51 patients did not. The overall success rate was 85.8%, and no difference was noted between patients with and without CBCT (P=0.347). However, radiation dose (P=0.018) and sampling time (P=0.001) were significantly higher in patients who underwent CBCT than in patients who did not. In learning group, CBCT improved success rate from 62.5% to 96.4% (P=0.028), whereas it was not found in the proficiency group (P=0.693). Additionally, success rate in patients with an atypical RAV imaging pattern was significantly higher when CBCT was used than when it was not used (P=0.041), whereas no difference was noted in patients with typical RAV imaging pattern (P=0.511).Conclusion: For physicians not very experienced doing AVS, there is a clear significant improvement in success rate when CBCT is used. However, CBCT only has minimal benefit for experienced operators, meanwhile CBCT may take an extra time and increase the radiation dose during AVS.
“Frequent and Recurrent Emergency Department Visits: A State Level Analysis for Maryland, 2017-2019”
Authors: Kelekar Uma , Abdesslem Amel Ben , Tran Diep Thi Quynh , Shepherd Jewel , Turner Sidney Carl
Published: March 2022

Background
Frequent or repeat ED visits make up over 20% of the total ED visits, while frequent users constitute up to 8% of all ED users. While some studies have analyzed ED encounters over a single healthcare system, a single year or a condition, this study examines frequent and recurrent ED utilization for the state of Maryland over three years.
Methods
Using 2017–2019 State Emergency Department Databases (SEDD), we conducted bivariate and multivariate analyses and identified patient/community level characteristics associated with frequent (> 4 visits/year) and recurrent frequent ED users (two and three consecutive years) in Maryland.
Results
Of the total 5,331,843 ED visits, frequent visits were 24.4% (1,301,301) while frequent users made up 7.16% (234,973) of all ED users. Females [OR = 1.30, 95% CI 1.24, 1.36] and patients aged 21–44 [OR = 2.41, 95% CI 2.24,2.60] were more likely to visit the ED recurrently than males, children and adolescents respectively. Compared to those with private insurance and no chronic conditions, Medicaid beneficiaries were 2.41 (95% CI 2.24,2.60) and those with multiple chronic conditions was 2.34 [95% CI 2.14,2.54] times more likely to be recurrent frequent ED users respectively. The NH Blacks were 26% [95% CI 1.25,1.28] more likely to be frequent users than NH White patients while those from the lowest income quartile were 69% [95% CI 1.66,1.71] and 33% [95% CI 1.21,1.46] more likely to be frequent and recurrent frequent ED users compared to the highest income quartile. Compared to residents of large metropolitan areas, patients from micropolitan areas were 43% [95% CI 1.38,1.48] while those living further from an ED were 9% [95% CI 1.09, 1.10] were more likely to be frequent ED users.
Conclusions
Frequent and recurrent frequent ED users in the state of Maryland were associated with being female, 21–44 years old, NH Black, Medicaid beneficiaries, with multiple chronic conditions and reside in a lower income zip code. Frequent ED users were also more likely to reside micropolitan areas, and further from an ED facility. We propose recommendations to stakeholders to invest in care coordination and IT infrastructure, and expand community access to outpatient care.
Role of Indigenous and local knowledge in seasonal forecasts and climate risk preparedness: a case study of smallholder farmers in Chiredzi, Zimbabwe
Authors: Johnston Peter , Olagbegi Oladapo M. , Simpson Nicholas P. , Trisos Christopher H. , Zvobgo Luckson
Published: March 2022

Accessible, reliable and diverse sources of climate information are needed to inform anticipatory responses to climate change at all levels of society, particularly for vulnerable sectors such as smallholder farming. Globally, many communities use Indigenous knowledge (IK) and local knowledge (LK) to provide contextually calibrated and trusted forecasting information to guide livelihood choices, including on-farm decisions by smallholder farmers. Here, we examined the role of IK and LK in seasonal forecasting, preparedness, and broader climate adaptation decision-making of smallholder farmers in Chiredzi, Zimbabwe. Data was collected from 100 smallholder farmers through face-to-face semi-structured interviews in the month before the rainy season onset when preparatory decisions about planting were being made. Seventy-three percent (73%) of the interviewed farmers are using IK and LK-based climate forecasts, and 32% (of 73%) farmers rely on IK and LK only for climate risk preparedness decision-making. Binary logistic regression found the use of IK and LK climate forecasts by farmers was strongly predicted by farmers’ age and farm size with p = 0.009 and 0.017 respectively at p < 0.05 significance level. Farmers using IK and LK forecasts are implementing, on average triple, the number of adaptation measures compared to farmers not using IK and LK. These findings emphasise the accessibility and reliability of IK and LK for seasonal forecasts and demonstrate the close link between use of IK and LK and the implementation of adaptation actions. Recognition, inclusion and preservation of IK and LK are important to ensure its potential role in informed responses to climate change.
Low Triphenyl phosphate concentrations fuel proliferation and migration of Hep3B, a hepatocellular carcinoma cell line
Authors: Zhou Shuqing , Ye Liang , Zhang Xu , Wang Peng , Zhang Ying , He Shujiao , Li Yang , Li Shao , Liang Kangyan , Liao Shuguang , Gao Yi , Peng Qing
Published: March 2022

Organophosphate flame retardants (OPFRs) have been widely used due to their unique properties. The OPFRs are mainly metabolized in the liver. However, whether the OPFRs in human plasma mediate progression of liver cancer remains unclear. Triphenyl phosphate (TPP) is one of the OPFRs that are most detected in environmental matrices. In this study, we performed CCK8, ATP, and EdU analyses to evaluate the effect of TPP (0.025–12.8µM concentration) on proliferation, invasion, and migration of Hep3B, a hepatocellular carcinoma cell line. Tumor-bearing mouses model were used for in vivo validation. The results showed that relative low concentrations (0.025 to 0.1µM) slightly increased cell proliferation and remarkably promoted cell invasion and migration of Hep3B. Animal experiments confirmed that TPP treatment significantly enhanced tumor growth in the xenograft HCC model. To explore the possible molecular mechanisms that might be mediating the actions of TPP on Hep3B, we profiled gene expression in groups treated with or without TPP (0.05 and 0.1µM) using transcriptional sequencing. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Protein-Protein Interaction (PPI) analyses demonstrated that pathways affected by differentially expressed genes (DEGs) were mainly in nuclear-transcribed mRNA catabolic processes, cytosolic ribosome and ATPase activity. 0.05 and 0.1µM TPP led to up-regulation of a series of genes including EREG, DNPH1, SAMD9, DUSP5, PFN1, CKB, MICAL2, SCUBE3, and CXCL8, but suppressed the expression of MCC. These genes have been shown to be associated with proliferation and movement of cells. Together, our findings suggest that relatively low concentrations of TPP could fuel the proliferation, invasion, and migration of hepatocellular carcinoma cells. Thus, TPP might be a risk factor in the progression of hepatocellular carcinoma in humans.
Molecular Identity Changes of Tumor-Associated Macrophages and Microglia after MRgFUS induced BBB Opening in a Mouse Glioblastoma Model
Authors: Zhang Yanrong , Wang Jing , Ghobadi Sara , Zhou Haiyan , Huang Ai , Gerosa Marco , Hou Qingyi , Keunen Olivier , Golebiewska Anna , Habte Frezghi G. , Grant Gerald A. , Paulmurugan Ramasamy , Lee Kevin S. , Wintermark Max
Published: March 2022

An orthotopically xenografted mouse GL26 glioma model (Ccr2RFP/wt-Cx3cr1GFP/wt) was used to evaluate the effect of transient, focal opening of the Blood Brain Barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). Opening of the BBB was induced by Magnetic Resonance Imaging (MRI)-guided focused ultrasound (MRgFUS) combined with systemically-administered microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors and in peritumoral tissue were quantified utilizing cell counting in fluroscent, microscopic images. Tumors in animals treated with a single session of MRgFUS did not show significant changes in CX3CR1-GFP or CCR2-RFP cell numbers when compared to tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS showed significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells.The effect of MRgFUS on immune cell compositon of tumors and the brain parenchyma was also characterized and quantified utilizing flow cytometry. Glioma implantation resulted in increased amounts of monocytes, blood-derived macrophages, and microglia-derived macrophages in the brain parenchyma. Tumors administered MRgFUS showed increased numbers of monocytes and blood-derived macrophages. In addition, MRgFUS-treated tumors exhibited more CD80+CD206- cells in monocytes, blood-derived macrophages, microglia, and microglia-derived macrophages, and fewer CD80-CD206+ cells in monocytes and microglia. This signature is indicative of a shift toward a more pro-inflammatory polarization. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes, and induce a shift towards a more proinflammatory status of the immune environment in glioblastoma.
The validation of the EKFC equation for Glomerular Filtration Rate estimation and comparison with the Asian Modified CKD-EPI equation in Chinese Chronic Kidney Disease patients in the external study
Authors: Xie Peng , Zhao Li , Li Huan-li , Liu Hui-jing , Ma Jin , Huang Jian-min , Wei Ling-ge
Published: March 2022

Objective To verify whether a Modified Full Age Spectrum Creatinine-Based Equation (EKFC equation) is more applicable than the Asian Modified CKD-EPI equation in the clinical practice, which was confirmed with higher accuracy in estimating Glomerular Filtration Rate (GFR) in our external Chronic Kidney Disease (CKD) populations.Methods According to the EKFC equation and the Asian Modified CKD-EPI formula, we calculated estimated GFREKFC and GFRCKD-EPI, separately. Clinical diagnostic performance of the two equations was assessed and compared by correlation coefficient, regression equation, Bland–Altman analysis, bias, precision, accuracy(P30) and the incorrectly reclassified index under the premise of 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) dual plasma sample clearance method as reference method for GFR measurement (mGFR).Results Totally, 160 CKD patients were recruited in our external cohort. The GFREKFC was highly related with mGFR, with the correlation coefficient of 0.95 [95%CI, 0.93-0.96], (P<0.01) and regression equation of GFREKFC= mGFR*0.87+5.27. Compared with the Asian Modified CKD-EPI equation, the EKFC equation demonstrated a wider bias（-1.64 vs 0.84 ml/min/1.73 m2, P<0.01）, nearly identical precision (12.69 vs 12.72 ml/min/1.73 m2, P=0.42) and P30 (80.0% vs 74.4%, P=0.57). Furthermore, the 95% limit of agreement in Bland-Altman analysis of the two target equations were almost same (42.4 vs 44.4 ml/min/1.73 m2). And, the incorrectly reclassified index among the different CKD stages between the two models was not statistically different.In the mGFR≤60 ml/min/1.73 m2 subgroup analysis, the precision of the EKFC equation was better than the Asian Modified CKD-EPI formula (9.78 vs 10.25 ml/min/1.73 m2, P<0.01), and the bias and P30 were not statistically different. However, in the mGFR>60 ml/min/1.73 m2 subgroup, the EKFC equation did not performed better than the Asian Modified CKD-EPI formula with a wider bias (-8.60 vs -0.42 ml/min/1.73 m2, P<0.01), an inferior precision (16.39 vs 15.86 ml/min/1.73 m2, P<0.01), and a statistically invalid P30 (95.7% vs 94.2%, P=1.00).Conclusion The total performance of the EKFC equation is acceptable. However, compared with the Asian Modified CKD-EPI equation, the EKFC equation is not more accurate to estimate GFR in our external Chronic Kidney Disease populations.
Determination of transverse isotropic elastic constants of nacre and constituent tablets based on genetic-algorithm- assisted resonant ultrasound spectroscopy
Authors: Yamamoto Go , Matsui Kazuma , Yuki Shuma , Suk Ji Won
Published: March 2022

Novel classes of tough composites inspired by natural biological materials like nacre, which possesses a multiscale structure with a lamellar microarchitecture, have attracted significant attention for use in structural and energy-related applications. The current theoretical understanding of the toughening and deformation mechanisms of nacre, which could serve as guidelines for composite development, is based on limited material parameters. Here, we report an experimental and numerical study on the transverse isotropic elastic constants of nacre and its constituent inorganic tablets based on genetic-algorithm-assisted resonant ultrasound spectroscopy. The results show that, among the five elastic constants measured, the out-of-plane and in-plane Young’s moduli of nacre sampled from Pinctada martensii were 72.3 and 74.8 GPa, respectively. The remaining out-of-plane and in-plane Poisson’s ratios and out-of-plane shear modulus were 0.23, 0.24, and 21.3 GPa, respectively. Similar trends were observed for the constituent tablets, however, the Young’s moduli were slightly higher at 72.7 and 75.0 GPa, respectively. These results concerning the transverse isotropic elastic properties of nacre and its constituent tablets aid in realizing the bio-duplication of novel nacreous composite materials.
The effect of the magnetic field on the coupling between the sublevels of rubidium-87 D1 line and the circularly polarized light
Authors: Ebrahimi Mohaddese , Tabatabaei Seyeed Mojtaba , Tehranchi Mohammad Mehdi
Published: March 2022

The degree of Zeeman splitting of ground-state sublevels in the presence of a magnetic field can be measured using atomic sensors. The coherence of the spins in the ensemble affects the efficiency of an atomic magnetometer. The sensitivity of these sensors depends on the line width of the magnetic resonance curve, which is related to the coherence lifetime of the atomic spins. Atomic polarization influences the optical properties of the medium, making it anisotropic. The relatively long lifetime of ground-state polarization is a useful tool for measuring the energy-level splitting. The modification associated with the atomic coherence in the presence of an external magnetic field leads to interesting absorption effects in the atomic environment. The splitting of magnetic sublevels and the transition between them under the application of a magnetic field are quantum mechanical images of the interaction between a field and an atomic spin that must be analyzed using a density matrix. In the present work, magneto-optical effects with circularly polarized light such as the dynamic properties and evolution of sublevels of the rubidium-87 D1 line and the absorption properties of the atomic polarized environment are studied theoretically using the reduced density matrix approach.
Comparing Obstructive Versus Central Apneas in Obesity of Sleep—A Nationwide Population-Based Case Control Study
Authors: Chien Wu-Chien , Huang Shi-Hao , Chung Ren-Jei , Chung Chi-Hsiang , Wang Bing-Long , Sun Chien-An , Lin I-Long , Huang Yao-Ching , Tang Shih-En
Published: March 2022

Objectives: This study used a case control Study to compare whether obstructive sleep apnea (OSA) or central sleep apnea (CSA) are related with an increased risk of obesity.Materials and Methods: We used 2005 Longitudinal Health Insurance Database (LHID2005), which is part of the Taiwan National Health Insurance Research Database (NHIRD) to identified 24 363 obese patients; 97 452 patients without obesity were identified also, from the same database from January 1, 2000, to December 31, 2015. Age, sex, and index date were matched. Multiple logistic regression was used to analyze the previous exposure risk of OSA or CSA with obesity and. A p value of <.05 was considered significant.Results: Obesity patients have higher risk to be exposed to OSA than did those with CSA (OSA adjusted OR [AOR] = 2.927, 95% CI = 1.878-4.194, p < .001; CSA adjusted OR [AOR] = 2.234, 95% CI = 1.483-4.380, p < .001). Furthermore, the closeness of the exposure period to the index time was positively associated with the severity of obesity, with a dose–response effect (OSA exposure <1 year, AOR = 3.895; OSA exposure ≥1 year and <5 years, AOR = 2.933; OSA exposure ≥5 years, AOR = 2.486 ; CSA exposure <1 year, AOR = 2.484; CSA exposure ≥1 year and <5 years, AOR = 2.105; CSA exposure ≥5 years, AOR = 1.862). The exposure duration of OSA in patients with obesity was 2.927 times than that of CSA was 2.234 times. Longer exposure durations were associated with more severe obesity with a dose–response effect (OSA exposure <1 year, AOR = 2.251; OSA exposure ≥1 year and <5 years, AOR = 2.986; OSA exposure ≥5 years, AOR = 3.452; CSA exposure <1 year, AOR = 2.101; CSA exposure ≥1 year and <5 years, AOR = 2.207; CSA exposure ≥5 years, AOR = 2.976).Conclusions: OSA patients have significantly higher risk of Obesity than that of CSA in this study. Longer exposure to OSA or CSA was related with a higher likelihood of obesity, with a dose-response effect.
Genome-Wide Profiling of a Prognostic RNA-Binding Protein Signature in Esophageal Cancer
Authors: Zhang Guoqing , Zhang Yan , Yang Hang , Guo Yanan , Li Jindong , Li Xiangnan
Published: March 2022

Background
the roles of RNA-binding proteins (RBPs) in esophageal cancer (EC) need elucidation.
Materials and methods
The gene expression profiles and clinical data of patients with EC were downloaded from the Xena database. Candidate genes were obtained by taking the union of RBP genes, KEGG pathway-related genes and differentially expressed RBP genes from cluster analysis. Hub genes were extracted by PPI network construction.
Result
We built a Cox proportional hazards regression model with 7 prognostic RBPs (TRMT2A, PDHA1, MPRIP, KRI1, IL17A, HSPA1A and HIST1H4J). The risk score of each patient in the internal and external dataset cohorts was calculated and then the patients were divided into two groups based on the median. There were significant differences between the RBP risk score and response to chemotherapy, with low-risk patients being more likely to achieve CR. Finally, the risk score was revealed to be significantly related to OS by univariate and multivariate analyses, and pathological stage could also be used independently to predict the prognosis of EC.
Conclusion
Our study indicated that the RBP signature could serve as a prognostic biomarker of EC and provide new insight into chemoresistance in EC patients.
σ2R/TMEM97 in Retinal Ganglion Cell Degeneration
Authors: Wang Hua , Peng Zhiyou , Li Yiwen , Sahn James J. , Hodges Timothy R. , Chou Tsung-Han , Liu Qiong , Zhou Xuezhi , Jiao Shuliang , Porciatti Vittorio , Liebl Daniel J. , Martin Stephen F. , Wen Rong
Published: March 2022

The sigma 2 receptor (σ2R) was recently identified as an ER (endoplasmic reticulum) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that compounds that bind to σ2R/TMEM97 are neuroprotective, suggesting that σ2R/TMEM97 is involved in pathways leading to neurodegeneration. We explore the role of σ2R/TMEM97 in neurodegeneration by characterizing ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97−/− mice and demonstrate that in the absence of σ2R/TMEM97, RGCs are resistant to degeneration. In addition, we show that DKR-1677, a selective σ2R/TMEM97 ligand, significantly protects RGCs from ischemia-induced degeneration in wildtype mice. These results provide conclusive evidence that σ2R/TMEM97 plays a significant role in RGC death to facilitate neurodegeneration following ischemic injury. Blocking the function of σ2R/TMEM97 thus is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σ2R/TMEM97 in RGCs and likely in other σ2R/TMEM97-expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches to treat RGC degenerative diseases by inhibiting σ2R/TMEM97.
Effects of High Pressure-Assisted Extraction on Yield, Antioxidant, Antimicrobial and Anti-Diabetic Properties of Chlorogenic Acid and Caffeine Extracted From Green Coffee Beans
Authors: Lin Yan-Han , Huang Hsiao-Wen , Wang Chung-Yi
Published: March 2022

The bioactive ingredients of green coffee beans were extracted using high pressure-assisted extraction (HPE) and compared against those derived from the traditional heat reflux (HR) extraction method. The effect of extraction conditions on the extraction efficiency of functional components (chlorogenic acids, caffeine, total phenols, and flavonoids); the free radical-scavenging activity of the extract; and the inhibition of α-glucosidase, α-amylase, and food pathogenic bacteria were measured. Using water as the solvent, the high-pressure extraction rates of chlorogenic acid (CGA) and caffeine were 3.20–5.75 mg/100 g and 4.32–7.95 mg/100 g, respectively, which were significantly higher than the rates obtained using the traditional method (2.92 mg/100 g and 3.54 mg/100 g, respectively). Under optimal extraction conditions of 25°C and 600 MPa for 2.5 min, inhibition of α-glucosidase and α-amylase by the extract reached rates of 27% and 26%, respectively, with the highest free radical-scavenging activity of 81.5%. HPE samples exhibited antibacterial activity against both gram-positive (Staphylococcus aureus and Listeria innocua) and gram-negative (Escherichia coli and Salmonella enterica) bacteria, and the lowest minimum inhibitory concentration (4.69 mg/mL) against S. aureus was achieved. Scanning electron microscopic observations evidenced that high pressure partially damaged the intercellular compartments of coffee beans, increased solvent permeability, and improved the extraction rate of bioactive ingredients. The outcomes of the study demonstrated that, HPE can be employed as an efficient extraction technique for production of chlorogenic acids and caffeine that might have a potential application in food and related industries.
Machine Learning Model for Predicting Antibiotic Resistance in the Emergency Department in Patients With Urinary Tract Infection
Authors: Lee Hyun-Gyu , Seo Youngho , Han Seung Baik , Kim Ji Hye , Im Jae Hyoung , Durey Areum
Published: March 2022

Background: Increasing antimicrobial resistance in uropathogens is a clinical challenge to emergency physicians as antibiotics should be selected before an infecting pathogen or its antibiotic resistance profile is confirmed. This single-center retrospective study evaluated patients diagnosed with upper urinary tract infection (UTI) in the emergency department (ED) between January 2020 and June 2021 to develop a predictive model for antibiotic resistance of uropathogens, using machine learning (ML) algorithmsResults: Forty variables were used to train the model for predicting resistance to ciprofloxacin and the presence of ESBL of urinary pathogens. Model performance with the XGBoost Gradient-Boosted Decision Tree (GBDT) was compared with that of empirical treatment (ET) according to effectiveness of antibiotic selected and appropriateness of selection with respect to antibiotic stewardship. Two prediction models using different decision thresholds were developed. The probability of using ineffective antibiotics in the ED was significantly lowered by 13.3% in the GDBT 0.25 using a decision threshold of 0.25 than in the ET model. Further, the rate of appropriate use of narrow-spectrum antibiotics was higher by 7.4 times in the GBDT 0.44 model than in the ET model, while the ineffectiveness level was maintained.Conclusions: An ML model is potentially useful for predicting antibiotic resistance, improving the effectiveness and appropriateness of empirical antimicrobial treatment in patients with upper UTI in the ED. The model could be a point-of-care decision support tool to guide clinicians towards individualized antibiotic prescription.
Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: preliminary pharmacokinetics and pharmacodynamic data
Authors: Kleiber Niina , Remy Amandine , Tran Thai Hoa , Dubois Josée , Lapointe Chantal , Gavra Paul , Garcia-Bournissen Facundo , Théorêt Yves , Winikoff Rochelle
Published: March 2022

Extensive venous malformations (VM) involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. Patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Current pharmacological VM treatments (e.g. sirolimus) are not universally effective as 10% of patients present intractable debilitating and/or critical disease. Novel therapies are therefore highly needed for treatment-resistant VM. Over 70% of sporadic VM are attributed to activating mutations in the TEK gene, encoding the receptor tyrosine kinase TIE2 expressed by venous endothelial cells. Despite in vitro studies showing the superiority of alpelisib over sirolimus in inhibiting TIE2 signalling pathway and vein remodelling, there are currently no clinical reports of alpelisib use in VM. Our aim was therefore to assess the effect of alpelisib in TIE-2 mutated VM and to assess its pharmacokinetics. Three patients with a VM harboring the TEK L914F mutations were treated with alpelisib in an open-label compassionate use study. All patients experienced significant improvement. Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy showed dramatic improvement. Drug exposure was highly variable despite similar weight-adjusted doses, suggesting that alpelisib dosing should be individualized to patient’s characteristics and guided by therapeutic drug monitoring to improve clinical response.
AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy
Authors: Dent Paul , Booth Laurence , Roberts Jane L. , Poklepovic Andrew , Martinez Jennifer , Cridebring Derek , Reiman Eric
Published: March 2022

Background
We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells.
Methods
In vitro cell culture; in-cell immunostaining using a Hermes wide-field microscope with densitometric imaging software; transfection of siRNA and plasmids; assessments of autophagy using a plasmid to express LC3-GFP-RFP.
Results
AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation.
Conclusions
We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.
Attention-LSTM Based Prediction Model for Aircraft 4-D Trajectory
Authors: Jia Peiyan , Chen Huiping , Zhang Lei , Han Daojun
Published: March 2022

With the increase of aviation activities, airspace constraints and flight delays have become increasingly prominent in the process of air traffic management (ATM). How to increase airspace capacity within the limited airspace resources while ensuring smooth and safe aircraft operations is a challenge for civil aviation today. In order to accelerate the intelligent operation of air traffic control and promote the development of intelligent ATM systems, it becomes very important to improve the accuracy of trajectory prediction, which becomes very difficult due to the problems of sparse aircraft flight trajectory and different flight altitudes. In order to solve this problem, an Attention-LSTM trajectory prediction model is proposed in this paper. This model can extract the time series features of the trajectory using an long short-term memory (LSTM) network and improve the accuracy of trajectory prediction by extracting the important factors affecting the current point change using an attention mechanism. To verify the accuracy of our proposed model, this paper uses real trajectory data, and uses LSTM, support vector machine, and other models for comparison. The comparison results show that this model is better than the most advanced model, which further promotes the process of intelligent ATM systems.
Segregated transmission of co-occluded baculoviruses limits cellular coinfection and virus-virus interactions
Authors: Pazmiño-Ibarra Verónica , Herrero Salvador , Sanjuán Rafael
Published: March 2022

Baculovirus occlusion bodies (OBs) are polyhedrin-rich structures that mediate the collective transmission of tens of viral particles to the same insect host. In addition, in multiple nucleopolyhedroviruses, occlusion-derived viruses (ODVs) form nucleocapsid aggregates that are delivered to the same host cell. It has been suggested that, by favoring coinfection, this transmission mode promotes evolutionarily stable interactions between different baculovirus variants. To investigate this, we obtained OBs from cells coinfected with two viral constructs, each encoding a different fluorescent reporter, and used them for inoculating Spodoptera exigua larvae. Microscopy analysis of midguts revealed that the two reporter genes were typically segregated into different infection foci, suggesting that ODVs do not promote the coinfection of cells with different baculovirus genetic variants. However, a polyhedrin-deficient mutant underwent inter-host transmission by exploiting the OBs of a fully-functional virus and re-acquired the lost gene through recombination, demonstrating cellular coinfection. Our results suggest that viral spatial segregation during transmission and primary infection limits interactions between different baculovirus variants, but that these interactions still occur episodically.
Joint effect of Maternal Pre-pregnancy Body Mass Index and Folic Acid Supplements on Gestational Diabetes Mellitus Risk: A prospective cohort study
Authors: Li Minyu , Wang Lijiang , Du Zhanhui , Shen Qianqian , Jiang Lu , Sui Lun , Zhang Nan , Wang Hong , Li Guoju
Published: March 2022

Background: The joint effect of folic acid (FA) supplements and maternal pre-pregnancy body mass index (ppBMI) on gestational diabetes mellitus (GDM) has not been fully addressed. We aimed to examine the joint effect of FA supplements and ppBMI on GDM.Methods: Pregnant women at 4 to 14 weeks of gestation (n=3186) were recruited to this study during their first prenatal visit in Qingdao from May 1, 2019, to June 27, 2021. The main outcome was GDM and GDM screening based on 75g 2-hour OGTT, a fasting glucose ≥5.1 mmol/L, or a 1-hour result ≥10.0 mmol/L, or a 2-hour result ≥8.5 mmol/L at 24-28 weeks’ gestation. The interactive effect of FA supplements and ppBMI on GDM was examined by logistic regression models.Results: A total of 2095 pregnant women were included analysis, and GDM incidence was 17.76%. The joint effect of ppBMI and FA supplements was statistically significant on GDM. The risk effect was most prominent among pregnant women with FA-D and pre-pregnant obese (adjusted OR [aOR]=5.10, 95% CI: 1.83-14.19). This synergistic effect was more obvious when stratified by FA intake time. The aORs of FA-S and FA-D among the obesity women were 2.75 (95% CI: 1.42-5.34) vs. 4.49 (95% CI: 1.22-16.50) in FA intake <3 months. An increased risk of GDM was more apparent for obesity women with FA-D in FA intake ³3 months (aOR=9.83, 95%CI: 1.52-63.47). However, as for pre-pregnant overweight, FA-D appeared to be positively associated with GDM only in the group of FA supplements ³3 months (aOR= 2.13, 95% CI: 1.46-3.11).Conclusion: Coexistence of pre-pregnancy overweight or obese and deficiency of FA supplements increased risk of GDM compared with each of these risk factors alone. Public awareness about the risk effects of FA deficiency, especially among pregnant women with a higher BMI, are necessary.
Cross-National Comparison Of Religion As A Predictor Of COVID-19 Vaccination Rate
Authors: Trepanowski Radosław , Drążkowski Dariusz
Published: March 2022

We examined the effects of religiosity on COVID-19 vaccination rate using a cross-national comparison while controlling for socio-economic factors and culture. Our analysis, conducted on data from 90 countries representing 86% of the world population showed that the proportion of Christians was negatively related with vaccination, while there was no relation with the proportion of Muslims, Buddhists, Hindus, and nonbelievers. The importance of religion, freedom of expression and belief, sex ratio, median age, and almost all cultural factors were not related to vaccination, whereas Human Development Index was. The influence of different religions on vaccination rate has also been described.
Proving Riemann Hypothesis by Elementary Equivalents
Authors: Kader Syed Abdul
Published: March 2022

One of the most elusive unsolved problems of today is Riemann hypothesis. For long mathematicians have struggled to prove this problem, and also tried to devise an elementary version of the problem, proof of which indirectly proves Riemann hypothesis. In 2002 J. C. Lagarias published such an elementary version of the hypothesis which has been widely accepted as an elementary equivalent of Riemann hypothesis. This article attempts to prove Lagarias's condition, a proof of Guy Robin's inequality has also been provided in the end, any of which consequently proves Riemann hypothesis.
Indications and pivotal trials of the FDA approved small-molecular kinase inhibitors in cancer therapies with and without biomarker of cancer driver gene
Authors: Huang Yafang , Xiong Weiyi , Ma Li , Wu Hao
Published: March 2022

Background: Cancer precision medicine with biomarker of cancer driver gene (CDG) has been achieved by many small-molecular kinase inhibitors (SMKIs) approved by the US Food and Drug Administration (FDA). We characterized their indications and pivotal trials with and without CDG biomarker. Methods: Publicly available FDA documents were collected for all SMKI cancer drugs approved between January 2001 and December 2021. Characteristics of indication and pivotal trial were compared in terms of trends in the number of approval, special expedited development and review pathways as determined by the FDA, cancer types, line of treatment, trial design features. Results: We identified 62 SMKI cancer drugs with 150 indications approved by the FDA between 2001 and 2021. Of these, 55 indications (36.7%) were CDG biomarker-directed. There was a significant increase of 20.5% per year in the number of approved CDG biomarker-directed indications. CDG biomarker-directed indications were associated with significantly higher odds in receiving accelerated approval (odds ratio [OR] = 2.728; 95% CI, 1.246 to 5.973; P = .012), designating orphan drug (OR = 3.952; 95% CI, 1.758 to 8.883; P < .001) and in solid cancer (OR = 7.613; 95% CI, 2.958 to 19.590; P < .001), and were associated with significantly lower odds in using randomized controlled trials (RCTs) (OR = 0.103; 95% CI, 0.032 to 0.338; P < .001) with less number of entered patients. In solid cancer, CDG biomarker-directed indications were associated with significantly higher overall response rates (ORRs). Conclusion: The number of CDG biomarker-directed indications in approved SMKIs increased significantly in past two decades, with higher proportion of approvals using special expedited development and approval pathways at the FDA, less proportion of trials with RCT, less number of entered patients but better ORRs.
A Prospective Cohort Study: Platelet-Rich Plasma Combined with Carpal Tunnel Release Treating Carpal Tunnel Syndrome short (running) title: PRP-CTR Treating Carpal Tunnel Syndrome
Authors: Chen Hua , Gao Yan-chun , Wang Qi-yang , Wang Chen-chen
Published: March 2022

Background: PRP injection was proved to promote the health condition of individuals with mild to moderate Carpal Tunnel Syndrome （CTS）. However, carpal tunnel release (CTR) was still an important treatment for individuals with moderate, as well as severe CTS.Methods: To explore whether adjuvant PRP treatment would improve the prognosis while using CTR, we included 82 patients in this study. Preoperative and postoperative visual analog scale (VAS), Boston carpal tunnel syndrome questionnaire-symptom severity scale (BCTQ-SSS), Boston carpal tunnel syndrome questionnaire-functional status scale (BCTQ-FSS), and grip strength was used to examine the patient's symptoms and function.Results: CTR combined with PRP treatment improved the VAS (1.9±0.5 versus 1.4±0.4, P<.05), BCTQ-SSS (1.8±0.4versus 1.5±0.3, P<.05) and BCTQ-FSS (1.8±0.5 versus 1.4±0.6, P<.05) in patients with moderate symptoms within one month after surgery. At the same time, it does not show any advantages in treating individuals with severe carpal tunnel syndrome.Conclusions: The use of PRP does not affect long-term prognosis while increasing the surgery cost. To conclude, PRP as an adjuvant treatment of CTR has limited effect. Considering the additional financial burden on patients, CTR combined with PRP should be cautious in CTS treatment.
The Gonial Angle as a Predictive Marker of Mandibular Fossa Depth: A Diagnostic Accuracy Study
Authors: KOLSUZ Mehmet Eray , BOZKURT Poyzan , SEKİ Umut
Published: March 2022

Purpose
The aim of the study is to evaluate the relationship between submandibular fossa depth and gonial angle measurements in cone beam computed tomography examinations in terms of dental implant applications and whether the results can be transferred to panoramic radiographs.
Methods
Cone-beam computed tomography images of 51 dry human mandibles were included. Gonial angle and fossa depths were determined and evaluated separately for left and right sides. Gonial angle was measured on Cone-beam computed tomography images as the angle between the tangent line drawn posterior to the border of the ramus of the mandible and the tangent line drawn to the lower border of the mandible. Determination of the submandibular fossa depth was made with a line was drawn to connect the most dislocated upper and lower points on the inner surface of the mandible in the coronal plane sections, and the length of the line drawn at a right angle from the deepest point of the fossa to this line. Measurements were made separately for left and right sides.
Results
No statistically significant correlation was found between the angle measurement and the depth measurements from the left and right sides. There was no statistically significant correlation between mean angle measurement and mean depth measurement. No statistically significant correlation was found between all angle measurements and all depth measurements.
Conclusion
The mandibular gonial angle is not a suitable marker to be used to predict the depth of the submandibular fossa on panoramic radiographs.
Demography and Clinical Pattern of Newly Diagnosed Uveitis Patients in Malaysia
Authors: Rajan Rajasudha Sawri , Mohamed Shelina Oli , Salowi Mohamad Aziz
Published: March 2022

Introduction:Uveitis is one of the common causes of visual impairment in Malaysia and it remains a challenging entity to diagnose and manage. This study aims to observe the demographic and clinical pattern of uveitis cases that are referred to most ophthalmology units in Malaysia Methods:This was an observational, multicenter study with a total of 1199 newly diagnosed uveitis patients. Data collected and analyzed included age, gender, ethnicity, nationality, state of origin, laterality, granulomatous or non-granulomatous uveitis, and etiology of uveitis.Results:The results showed that majority of the patients across all age groups had anterior uveitis (n=560; 46.7%). The higher the age group, the higher the percentage of anterior uveitis patients (39.0% among 20-40 age group vs 61.3% among the >60 age group). Sixty three percent of the patients presented with unilateral uveitis (n= 760, p <0.001). Non granulomatous uveitis comprised 84.5% of all patients (n=1013, p< 0.001). Non-infectious etiology contributed to 65.7% of all patients (n=788, p<0.001) with idiopathic (57.2%, n=686) as the most common cause followed by Vogt-Koyanagi-Harada (VKH) syndrome (2.1%, n=25). Infectious uveitis comprised 34.3% (411 patients) in total with Tuberculous (TB) related uveitis (105 patients with 8.8%) and Viral related uveitis (107 patients with 8.9%) contributing the most followed by Ocular Toxoplasmosis (n=93,7.8%). The likelihood of posterior uveitis being more infectious was statistically significant (Odds ratio (OR) 12.54, 95% CI 8.81-18.13) (p-value <0.001)Conclusion:This study has highlighted the demographic data and common causes of uveitis in Malaysia