bluuebunny/crossref_metadata_2025 huggingface dataset:
Disease‐Associated Circular RNAs: From Biology to Computational Identification
Authors: Tang Min , Kui Ling , Lu Guanyi , Chen Wenqiang
Published: August 2020

Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed continuous loop, generated through various backsplicing events of pre‐mRNA. An accumulating number of studies have shown that circRNAs are potential biomarkers for major human diseases such as cancer and Alzheimer’s disease. Thus, identification and prediction of human disease‐associated circRNAs are of significant importance. To this end, a computational analysis‐assisted strategy is indispensable to detect, verify, and quantify circRNAs for downstream applications. In this review, we briefly introduce the biology of circRNAs, including the biogenesis, characteristics, and biological functions. In addition, we outline about 30 recent bioinformatic analysis tools that are publicly available for circRNA study. Principles for applying these computational strategies and considerations will be briefly discussed. Lastly, we give a complete survey on more than 20 key computational databases that are frequently used. To our knowledge, this is the most complete and updated summary on publicly available circRNA resources. In conclusion, this review summarizes key aspects of circRNA biology and outlines key computational strategies that will facilitate the genome‐wide identification and prediction of circRNAs.
Geometric Inequalities via a Symmetric Differential Operator Defined by Quantum Calculus in the Open Unit Disk
Authors: Ibrahim Rabha W. , Elobaid Rafida M. , Obaiys Suzan J.
Published: August 2020

The present investigation covenants with the concept of quantum calculus besides the convolution operation to impose a comprehensive symmetric q-differential operator defining new classes of analytic functions. We study the geometric representations with applications. The applications deliberated to indicate the certainty of resolutions of a category of symmetric differential equations type Briot-Bouquet.
Forecasting Maternal Complications Based on the Impact of Gross National Income Using Various Models for Rwanda
Authors: Namahoro Jean Pierre , Mugabushaka Adrien
Published: August 2020

Introduction. Preferably maternal mortalities are predominant in low- and middle-income countries (LMICs). In some African countries, including Rwanda, programs related to health-care delivery to reduce significantly severe complications including mortalities are established. Unfortunately, historical and forecasted maternal mortality reduction and the influence of gross national income (GNI) were not accessed. This study is aimed to forecast the three years of maternal mortalities (MMs) based on the influence of gross national income (GNI) in Rwanda. Methods. The period involved is from January 2009 to April 2018. Data analyzed were obtained from the Central Hospital of the University of Kigali (CHUK) and mined data from the WHO database. Time series approach (Box-Jenkins and exponential smoothing) and linear regression models were applied. Besides, IBM-SPSS and Eviews were used in the analysis. Results. The results revealed that MMs were not statistically different in several years, and there was a significant correlation between MMs and GNI (-0.610, P value 0.012 < 0.05). A double exponential smoothing model (DESM) was fitted for the best forecast and ARIMA (0,1,0) and linear regression models for a quick forecast. Conclusion. There was a slight effect of GNI in maternal mortality reduction, which leads to the steady decrease of the forecasted maternal mortality up to May 2021. The Government of Rwanda should intensively strengthen the health-care system, save the children programs, and support pregnant women by using GNI for reducing MMs at an advanced level.
A Comparative Study on Structural, Morphological, and Tensile Properties of Binary and Ternary Epoxy Resin‐Based Polymer Nanocomposites
Authors: Mustafa Dalia M. T. , Rostam Sarkawt , Aziz Shujahadeen B.
Published: August 2020

In the present work, epoxy resin‐based nanocomposites (NCPs) were fabricated with improved mechanical properties. The epoxy resin (EPR) was mixed with differing amounts of calcium titanate (CaTiO3) nanoparticles (NPs) and glass fiber. The results showed that the ternary system contained glass fiber exhibits low mechanical performance compared to binary [EPR:CaTiO3] system. The effect of fiber glass and NPs on the epoxy resin mechanical behavior was determined by conducting a tensile test for various specimen sets. From the mechanical characterizations, it was seen that there is a monotonic relationship between the NPs concentration and Young’s modulus. Additionally, NCPs samples were brittle in nature and the strain rate significantly decreased upon the addition of CaTiO3 concentration; while the tensile strength was increased. From the X‐ray diffraction evaluation, it can be concluded that the addition of NPs have a great impact on the epoxy structure. Besides, the morphology appearance was in good agreement with structural and mechanical analysis.
Morphological Characteristics of Normal Foveal Avascular Zone by Optical Coherence Tomography Angiography
Authors: Eldaly Zeiad , Soliman Wael , Sharaf Mohamed , Reyad Ali Natag
Published: August 2020

Purpose. To provide quantitative measurements for the foveal avascular zone (FAZ) and to describe its morphological characteristics by optical coherence tomography angiography (OCT-A). Design. Cross-sectional observational case series. Methods. Healthy volunteers were recruited and evaluated using Triton-DRI SS-OCT Angiography. A 4.5 × 4.5 mm square was evaluated by OCT-A center around the fovea. Superficial and deep capillary plexus were identified, and different quantitative measurements were conducted along with categorization of the FAZ pattern. Results. Eighty-two eyes (41 volunteers) were evaluated. Mean age was 30.59 ± 7.6 years (23–42 years). Mean subcentral retinal thickness was 200.1 ± 5.66 um (192–210 um). The number of terminal vessels was variable (range, 8–11). Mean maximum terminal vessel-to-vessel intervening distance was 527.8 ± 60.3 um (471–674 um). Mean minimum terminal vessel-to-vessel intervening distance was 296.7 ± 45.8 um (233–373 um). Mean maximum horizontal diameter of FAZ (superficial) was 716.17 ± 124.09 um, while mean maximum vertical diameter of FAZ (superficial) was 667.76 ± 131.28 um. Mean maximum horizontal diameter of FAZ (deep) was 823.19 ± 144.92 um, while mean maximum vertical diameter of FAZ (deep) was 794.03 ± 150.28 um. OCT-A detected different FAZ patterns; horizontally oval configuration in 32 eyes (39%), rounded configuration in 24 eyes (29.3%), pentagon configuration in 14 eyes (17.1%), and vertically oval and nonspecific configuration in 6 eyes each (7.3%). Conclusion. OCT-A could efficiently provide both quantitative and qualitative assessment of normal FAZ; such characterizations were difficult by standard FAZ assessment procedures like FFA.
Iatrogenic Superior Vena Cava Syndrome after Cardiopulmonary Bypass Diagnosed by Intraoperative Echocardiography
Authors: Ellison Matthew B. , Statler Alex , Henrickson Roy E. , Graff Julia , Sloyer Daniel , Abbas Khan Mir Ali , Hayanga Heather K. , Ellison Pavithra R.
Published: August 2020

A 73-year-old female patient presented for mitral valve replacement and coronary artery bypass grafting secondary to multivessel coronary disease and severe mitral valve regurgitation with moderate stenosis. After bypass, the patient developed refractory hypotension with decreased biventricular volume and elevated central venous pressure (CVP). Transesophageal echocardiography (TEE) was utilized to make the diagnosis of acute intraoperative superior vena cava (SVC) syndrome. The SVC cannulation site was revised, resulting in resolution of the hypotension and a decrease in the CVP. Intraoperative TEE was vital in recognizing, managing, and ultimately repairing the acute intraoperative SVC stenosis.
A Homomorphic Encryption and Privacy Protection Method Based on Blockchain and Edge Computing
Authors: Yan Xiaoyan , Wu Qilin , Sun Youming
Published: August 2020

With its decentralization, reliable database, security, and quasi anonymity, blockchain provides a new solution for data storage and sharing as well as privacy protection. This paper combines the advantages of blockchain and edge computing and constructs the key technology solutions of edge computing based on blockchain. On one hand, it achieves the security protection and integrity check of cloud data; and on the other hand, it also realizes more extensive secure multiparty computation. In order to assure the operating efficiency of blockchain and alleviate the computational burden of client, it also introduces the Paillier cryptosystem which supports additive homomorphism. The task execution side encrypts all data, while the edge node can process the ciphertext of the data received, acquire and return the ciphertext of the final result to the client. The simulation experiment proves that the proposed algorithm is effective and feasible.
Research on Fatigue Damage in High-Strength Steel (FV520B) Using Nonlinear Ultrasonic Testing
Authors: Chen Bingbing , Wang Chao , Wang Pengfei , Zheng Sanlong , Sun Weiming
Published: August 2020

In view of the early fatigue damage of high-strength steel FV520B, a nonlinear ultrasonic detection was performed on two types of fatigue samples using nonlinear Lamb waves. The experimental results indicated that the ultrasonic nonlinear parameter is highly sensitive to early fatigue damage in high-strength FV520B. For plate specimens, the ultrasonic nonlinear parameter increased with the number of fatigue cycles. Scanning electron microscopy (SEM) observations of the fatigue specimens revealed that as the number of fatigue cycles increased, the microstructure of the material gradually deteriorated, and the ultrasonic nonlinear parameter increased. For notched specimens, the ultrasonic nonlinear parameter increased as the size of the main crack increased. SEM observations of the fracture indicated that the ultrasonic nonlinear parameters were more consistent with the equivalent microcrack length (defined as the sum of microcrack lengths in the statistical area), as compared with the length of the main crack. It was determined that the nonlinear effect of the Lamb wave is related to the equivalent microcrack length inside the material and that the ultrasonic nonlinear parameter can effectively characterize the fatigue damage state of high-strength FV520B.
Dental Pulp Mesenchymal Stem Cells as a Treatment for Periodontal Disease in Older Adults
Authors: Hernández-Monjaraz Beatriz , Santiago-Osorio Edelmiro , Ledesma-Martínez Edgar , Aguiñiga-Sánchez Itzen , Sosa-Hernández Norma Angélica , Mendoza-Núñez Víctor Manuel
Published: August 2020

Periodontal disease (PD) is one of the main causes of tooth loss and is related to oxidative stress and chronic inflammation. Although different treatments have been proposed in the past, the vast majority do not regenerate lost tissues. In this sense, the use of dental pulp mesenchymal stem cells (DPMSCs) seems to be an alternative for the regeneration of periodontal bone tissue. A quasi-experimental study was conducted in a sample of 22 adults between 55 and 64 years of age with PD, without uncontrolled systemic chronic diseases. Two groups were formed randomly: (i) experimental group (EG) n=11, with a treatment based on DPMSCs; and a (ii) control group (CG) n=11, without a treatment of DPMSCs. Every participant underwent clinical and radiological evaluations and measurement of bone mineral density (BMD) by tomography. Saliva samples were taken as well, to determine the total concentration of antioxidants, superoxide dismutase (SOD), lipoperoxides, and interleukins (IL), before and 6 months after treatment. All subjects underwent curettage and periodontal surgery, the EG had a collagen scaffold treated with DPMSCs, while the CG only had the collagen scaffold placed. The EG with DPMSCs showed an increase in the BMD of the alveolar bone with a borderline statistical significance (baseline 638.82±181.7 vs. posttreatment 781.26±162.2 HU, p=0.09). Regarding oxidative stress and inflammation markers, salivary SOD levels were significantly higher in EG (baseline 1.49±0.96 vs. 2.14±1.12 U/L posttreatment, p<0.05) meanwhile IL1β levels had a decrease (baseline 1001.91±675.5vs. posttreatment 722.3±349.4 pg/ml, p<0.05). Our findings suggest that a DPMSCs treatment based on DPMSCs has both an effect on bone regeneration linked to an increased SOD and decreased levels of IL1β in aging subjects with PD.
Measurement of Cotton Canopy Temperature Using Radiometric Thermal Sensor Mounted on the Unmanned Aerial Vehicle (UAV)
Authors: Chang Anjin , Jung Jinha , Maeda Murilo M. , Landivar Juan A. , Carvalho Henrique D. R. , Yeom Junho
Published: August 2020

Canopy temperature is an important variable directly linked to a plant’s water status. Recent advances in Unmanned Aerial Vehicle (UAV) and sensor technology provides a great opportunity to obtain high-quality imagery for crop monitoring and high-throughput phenotyping (HTP) applications. In this study, a UAV-based thermal system was developed to directly measure canopy temperature, skipping the traditional radiometric calibration process which is time-consuming and complicates data processing. Raw thermal imagery collected over a cotton field was converted to surface temperature using the Software Development Kit (SDK) provided by the sensor company. Canopy temperature map was generated using Structure from Motion (SfM), and Thermal Stress Index (TSI) was calculated for the test site. UAV temperature measurements were compared to ground measurements acquired by net radiometers and thermocouples. Temperature differences between UAV and ground measurements were less than 5%, and UAV measurements proved to be more stable. The proposed UAV system was successful in showing temperature differences between the cotton genotype. In conclusion, the system described in this study could possibly be used to monitor crop water status in a field setting, which should prove helpful for precision agriculture and crop research.
Adaptive Evolution of Feline Coronavirus Genes Based on Selection Analysis
Authors: Xia Hongyue , Li Xibao , Zhao Wenliang , Jia Shuran , Zhang Xiaoqing , Irwin David M. , Zhang Shuyi
Published: August 2020

Purpose. We investigated sequences of the feline coronaviruses (FCoV), which include feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), from China and other countries to gain insight into the adaptive evolution of this virus. Methods. Ascites samples from 31 cats with suspected FIP and feces samples from 8 healthy cats were screened for the presence of FCoV. Partial viral genome sequences, including parts of the nsp12‐nsp14, S, N, and 7b genes, were obtained and aligned with additional sequences obtained from the GenBank database. Bayesian phylogenetic analysis was conducted, and the possibility of recombination within these sequences was assessed. Analysis of the levels of selection pressure experienced by these sequences was assessed using methods on both the PAML and Datamonkey platforms. Results. Of the 31 cats investigated, two suspected FIP cats and one healthy cat tested positive for FCoV. Phylogenetic analysis showed that all of the sequences from mainland China cluster together with a few sequences from the Netherlands as a distinct clade when analyzed with FCoV sequences from other countries. Fewer than 3 recombination breakpoints were detected in the nsp12‐nsp14, S, N, and 7b genes, suggesting that analyses for positive selection could be conducted. A total of 4, 12, 4, and 4 positively selected sites were detected in the nsp12‐nsp14, S, N, and 7b genes, respectively, with the previously described site 245 of the S gene, which distinguishes FIPV from FECV, being a positive selection site. Conversely, 106, 168, 25, and 17 negative selection sites in the nsp12‐14, S, N, and 7b genes, respectively, were identified. Conclusion. Our study provides evidence that the FCoV genes encoding replicative, entry, and virulence proteins potentially experienced adaptive evolution. A greater number of sites in each gene experienced negative rather than positive selection, which suggests that most of the protein sequence must be conservatively maintained for virus survival. A few of the sites showing evidence of positive selection might be associated with the more severe pathology of FIPV or help these viruses survive other harmful conditions.
Results of Neuroimaging in Patients with Atypical Normal‐Tension Glaucoma
Authors: Kosior-Jarecka Ewa , Wróbel-Dudzińska Dominika , Pietura Radosław , Pankowska Anna , Szczuka Beata , Żarnowska Iwona , Łukasik Urszula , Żarnowski Tomasz
Published: August 2020

Aim. The aim of the study was to determine the frequency of pathologies which can mimic normal‐tension glaucoma (NTG), observed in neuroimaging of NTG patients, and to evaluate the frequency of pathologies in determined additional indications for neuroimaging. Material and Methods. The studied group consisted of 126 NTG patients who met at least one of the following criteria: unilateral NTG, damage in the visual field (VF) inconsistent with optic disc appearance, fast VF progression, worsening of visual acuity, predominant optic disc pallor rather than optic disc excavation, diagnosis under the age of 50, and scotoma in VF restricted by a vertical line. The patients included in the research underwent MRI scans of the brain and both orbits. Results. After neuroimaging, the results of 29 (23%) patients were qualified as positive; 18 (14.2%) of the identified pathologies were found to clinically affect the visual pathway. The most frequent brain pathology was intracranial meningiomas, observed in 4 patients (3.1%), followed by optic nerve sheath meningiomas diagnosed in 3 cases (2.4%), and brain glioma in 1 patient (0.8%). Pituitary gland adenomas were described in 6 patients (4.5%); 3 of the tumours were in contact with the optic chiasm. 53 (40%) patients had minimal ischemic changes in different regions of the brain. In the case of worsening BCVA or fast VF progression, the frequency of positive results was the highest (50% and 40%), whereas in the case of diagnosis at a young age and unilateral involvement, neuropathology was the rarest (0% and 6.9%). Conclusions. In the case of NTG, the decision to perform neuroimaging should be made after a detailed assessment of clinical status, rather in the event of finding the signs of possible compressive optic neuropathy than as an obligatory procedure for every patient.
Cdkn2a Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST
Authors: Chaney Katherine E. , Perrino Melissa R. , Kershner Leah J. , Patel Ami V. , Wu Jianqiang , Choi Kwangmin , Rizvi Tilat A. , Dombi Eva , Szabo Sara , Largaespada David A. , Ratner Nancy
Published: August 2020

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST.

Significance:

New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.
Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR–TKI Tolerance and Lung Cancer Dissemination
Authors: Kuo Ming-Han , Lee An-Chun , Hsiao Shih-Hsin , Lin Sey-En , Chiu Yu-Fan , Yang Li-Hao , Yu Chia-Cherng , Chiou Shih-Hwa , Huang Hsien-Neng , Ko Jen-Chung , Chou Yu-Ting
Published: August 2020

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination.

Significance:

These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.
Morphology-Predicted Large-Scale Transition Number in Circulating Tumor Cells Identifies a Chromosomal Instability Biomarker Associated with Poor Outcome in Castration-Resistant Prostate Cancer
Authors: Schonhoft Joseph D. , Zhao Jimmy L. , Jendrisak Adam , Carbone Emily A. , Barnett Ethan S. , Hullings Melanie A. , Gill Audrey , Sutton Ramsay , Lee Jerry , Dago Angel E. , Landers Mark , Bakhoum Samuel F. , Wang Yipeng , Gonen Mithat , Dittamore Ryan , Scher Howard I.
Published: August 2020

Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes.

Significance:

A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.
Safety and Effectiveness of Omnitrope®, a Biosimilar Recombinant Human Growth Hormone: More Than 10 Years’ Experience from the PATRO Children Study
Authors: Pfäffle Roland , Bidlingmaier Martin , Kreitschmann-Andermahr Ilonka , Land Christof , Partsch Carl Joachim , Schwab Karl Otfried , Sommer Heide , Backeljauw Philippe , Kanumakala Shankar , Loche Sandro , Zouater Hichem , Strasburger Christian J.
Published: August 2020

Introduction: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Objective: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children – an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. Methods: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. Results: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0–133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). Conclusions: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.
Unusual Presentation of Mammary Calciphylaxis in a Patient on Long-Standing Renal Dialysis
Authors: Elghobashy Maiar , Vaquas Shams , Elshafie Mona , Kaneri Shekhar , Shaaban Abeer M.
Published: August 2020

Introduction: Calciphylaxis is a condition which involves ectopic deposition of calcium in arterioles of various organ systems. Here, we present a rare case of mammographic calcifications in a patient on long-standing renal dialysis. Case: This is a 57-year-old female who presented to breast clinic with unilateral severe pain and lumpiness of her breast. On mammography, calcifications were identified which were associated with focal lesions on ultrasound. An image-guided core biopsy showed numerous foci of histological calcification within a large area of fat necrosis. The location within arterioles was confirmed by CD31 immunohistochemistry. The diagnosis of fat necrosis with benign calcifications due to mammary calciphylaxis was made. Conclusion: The hallmark of calciphylaxis is the deposition of calcium within small- to medium-sized vessel walls. This leads to ischaemia and necrosis of tissue. In the breast, only a few cases were reported in which patients presented with a necrotic lesion resembling carcinoma. These are reviewed in this report.
Rapid Improvement of the Performance Status and Reduction of the Tumor Size in KRAS-Mutated Colorectal Cancer Patient Receiving Binimetinib, Hydroxychloroquine, and Bevacizumab
Authors: Orlov Sergey V. , Urtenova Magaripa A. , Sviridenko Maria A. , Nesterov Denis V. , Sokolova Tatiana N. , Imyanitov Evgeny N.
Published: August 2020

Activating RAS mutations occur in more than a half of colorectal cancers (CRCs). RAS-mutated CRCs are notoriously difficult to treat given that they are characterized by the aggressive disease course and the lack of appropriate targeted therapies. Recent preclinical studies demonstrated that RAS-mutated cells escape from therapeutic MEK inhibition by the development of autophagy, and this escape may be prevented by the administration of an antimalarial drug, hydroxychloroquine. The available clinical data are limited to a single case observation involving a patient with KRAS-mutated pancreatic cancer. Here, we report a woman with KRAS G12D-mutated CRC, whose tumor did not respond to conventional therapy. The combination of binimetinib, hydroxychloroquine, and bevacizumab was administered as a last-hope option. The patient experienced rapid improvement of the performance status. The tumor lumps demonstrated 17% reduction in the size within the first 6 weeks of the therapy. This report calls for evaluation of the efficacy of a combination of MEK inhibitors and hydroxychloroquine, possibly with the addition of bevacizumab, in chemotherapy-resistant patients with RAS-mutated cancers.
Delay in Treatment of Neonatal Seizures: A Retrospective Cohort Study
Authors: Apers Wievineke M.J. , de Vries Linda S. , Groenendaal Floris , Toet Mona C. , Weeke Lauren C.
Published: August 2020

Introduction: Neonatal seizures are common and caused by a variety of underlying disorders. There is increasing evidence that neonatal seizures result in further brain damage. Objective: To describe the time interval between diagnosis of amplitude-integrated electroencephalography (aEEG)-confirmed seizures and administration of anti-epileptic drugs (AEDs). Methods: Single-centre retrospective cohort study, with full-term infants (n = 106) admitted to a level III neonatal intensive care unit between 2012 and 2017 with seizures confirmed on 2-channel aEEG and corresponding raw electroencephalography traces, treated with AEDs. The time interval between the first seizure on the aEEG registration and AED administration was calculated. Factors associated with early treatment were analysed. Results: The median time interval of initiating treatment of aEEG-confirmed seizures was 01:50 h (interquartile range 00:43–4:30 h). Treatment of aEEG-confirmed seizures was initiated <1 h in 34/106 infants (32.1%), between 1 and 2 h in 21/106 infants (19.8%), 2–4 h in 23/106 infants (21.7%), 4–8 h in 14/106 infants (13.2%), and ≥8 h in 14/106 infants (13.2%). Seizures treated <1 h were significantly more often recognized by the seizure detection algorithm (SDA) compared to seizures treated >1 h (67 vs. 42%, p = 0.02) and showed more clinical signs (79.4 vs. 37.5%, p < 0.01). There was no difference for out-of-office hours (23.5 vs. 22.2%, p = 0.88). Conclusion: With only 32.1% of the seizures being treated <1 h, there is room for improvement. Timely treatment occurred more often when seizures were clinical or recognised by the SDA. aEEG is a helpful tool for diagnosing seizures 24/7.
Usefulness of Color Doppler Ultrasonography in the Risk Stratification of Thyroid Nodules
Authors: Maddaloni Ernesto , Briganti Silvia Irina , Crescenzi Anna , Beretta Anguissola Giuseppina , Perrella Eleonora , Taffon Chiara , Palermo Andrea , Manfrini Silvia , Pozzilli Paolo , Lauria Pantano Angelo
Published: August 2020

Introduction: Thyroid ultrasound (US) is crucial for clinical decision in the management of thyroid nodules. In this cross-sectional study, we aimed to test if the evaluation of thyroid nodules’ vascularization could improve the risk stratification ability of the American College of Radiology (ACR) TI-RADS classification system. Methods: A total of 873 thyroid nodules undergoing fine-needle aspiration were classified according to ACR TI-RADS US classification. Three types of vascularization were identified: type 0, no vascular signals; type 1, peripheral vascular signals; type 2, peripheral and intralesional vascular signals. Cytology specimens were evaluated conforming to the Italian Reporting System for Thyroid Cytology, and TIR3b, TIR4, and TIR5 were defined as high risk for malignancy. Odds ratios (ORs) with 95% confidence intervals (CI) and the areas under the receiver operating characteristic curves (ROC-AUC) for high-risk cytology categories were calculated. Results: The 3 vascular patterns were differently distributed within the cytology categories: 52.4% of TIR1c, 15.9% of TIR2, 5.9% of TIR3a, 6.7% of TIR3b, 12.5% of TIR4, and 28.9% of TIR5 nodules had no vascular signals (p < 0.001). Nodule vascularity alone was not associated with a higher risk of malignant cytology (OR [95% CI] 0.75 [0.43–1.32], p = 0.32), without differences between peripheral (OR [95% CI] 0.65 [0.35–1.20]) and intranodular (OR [95% CI] 0.88 [0.48–1.62]) vascularization (p = 0.22). The ROC-AUC (95% CI) for the diagnosis of malignant cytology was similar when considering TI-RADS classification alone (0.736 [0.684–0.786]) and when considering TI-RADS classification plus the presence/absence of vascular signals (0.736 [0.683–0.789], p value for differences between the ROC-AUCs: 0.91). Among TR1, TR2, and TR3 TI-RADS classes, no nodules without vascular signals showed a malignant cytology, allowing the identification of nodules with benign cytology with 100% specificity within these US classes. Conclusions: Color Doppler study of thyroid nodules does not improve the risk stratification ability of the ACR TI-RADS US classification system.
Management of Hypoglycemia in Adults with Type 1 Diabetes in Real-Life Condition
Authors: Murillo Serafín , Brugnara Laura , Maduell Xavier , Novials Anna
Published: August 2020

Introduction: Hypoglycemia is the most common acute complication in individuals with type 1 diabetes (T1D). Episodes of mild or moderate hypoglycemia should be treated in adults with a dose of around 15–20 g fast-acting carbohydrates. However, this self-treatment of hypoglycemia in real-life condition is not well documented. Objective: The aim of this study wasto determine the characteristics of hypoglycemia treatment in adults with T1D in a prospective study design. Methods: Individuals with T1D were advised to record information related to hypoglycemia episodes for a period of 14 days. Quantity and quality (including glycemic index [GI] and glycemic load) of carbohydrates consumed in every hypoglycemia episode and others factors related with hypoglycemia such as physical activity, fear of hypoglycemia, or hypoglycemia awareness were analyzed. Results: A total of 93 individuals (36.5 ± 16.2 years old, BMI of 24.9 ± 3.8 kg/m2, diabetes duration of 14.9 ± 10.4 years, and HbA1c levels of 7.3 ± 0.8%) were included in the study. A total of 483 episodes of mild or moderate hypoglycemia were reported, which supposed on average 2.7 ± 2.0 episodes a week. The quantity of carbohydrates consumed in all episodes of hypoglycemia was 25.9 ± 9.2 g. GI of food consumed in all episodes of hypoglycemia was classified as low (53.9 ± 8.3). Overtreatment of hypoglycemia, defined as ingestion of more than 20 g of carbohydrates, occurred in 50.3% of hypoglycemic episodes; even 22.3% of these episodes were treated with more than 30 g of carbohydrates. Fruit juice was the most popular option, chosen in almost 70% of the events. In addition, we observed other moderate or low GI foods such as milk, bread, cookies, and bakery products among the most consumed foods. Conclusion: A majority of the studied individuals with T1D does not manage hypoglycemia according to current American Diabetes Association guidelines, in most cases by overtreating, choosing foods with low glycemic effect, and not varying the dose of carbohydrates, depending on the physical activity performed.
Change of Health‐Related Quality of Life Over Time and Its Association With Patient Outcomes in Patients With Heart Failure
Authors: Sepehrvand Nariman , Savu Anamaria , Spertus John A. , Dyck Jason R. B. , Anderson Todd , Howlett Jonathan , Paterson Ian , Oudit Gavin Y , Kaul Padma , McAlister Finlay A. , Ezekowitz Justin A. ,   the Alberta HEART Investigators*
Published: August 2020

Background

Improving health‐related quality of life is an important goal in the management of patients with heart failure (HF). Defining health‐related quality of life changes over time in patients with HF with preserved (HFpEF) or reduced ejection fraction and showing their association with other important clinical events could support the use of health‐related quality of life as a measure of quantifying HF care.

Methods and Results

In the Alberta HEART (Heart Failure Aetiology and Analysis Team) cohort (n=621), patients were categorized into 4 subgroups: healthy controls (n=98), at risk (n=163), HFpEF (n=191), and HF with reduced ejection fraction (n=169). The change of the Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQOL 5 dimensions, and Functional Assessment of Cancer Therapy—Anemia over 12 months, and its association with a composite of death or rehospitalization within 3 years were assessed. At baseline, the KCCQ overall summary score was 73 (interquartile range, 53–86) in HFpEF and 78 (interquartile range, 56–90) in HF with reduced ejection fraction (
P
=0.22). Overall, 30.5% of patients with HF experienced ≥5‐point improvements and 32.4% had ≥5‐point worsening in KCCQ overall summary score at 12 months, which did not differ between HFpEF and HF with reduced ejection fraction (
P
=0.23). Clinical events were higher in patients with HF who had a decline in KCCQ over 12 months as compared with those with stable KCCQ scores (70.2% versus 52.0%,
P
=0.012). The results were similar for the Functional Assessment of Cancer Therapy—Anemia and EuroQOL 5 dimensions.

Conclusions

In patients with HF, the KCCQ quantified clinically meaningful changes over time, which were associated with important clinical outcomes in patients with HFpEF. Given the observed variability and prognostication in different patient trajectories, health‐related quality of life measures could be valuable for quantifying the quality of care in healthcare systems.
Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort
Authors: Dueker Nicole D. , Doliner Brett , Gardener Hannah , Dong Chuanhui , Beecham Ashley , Della-Morte David , Sacco Ralph L. , Blanton Susan H. , Wang Liyong , Rundek Tatjana
Published: August 2020

Background and Purpose:

Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort.

Methods:

Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with
P
<0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set.

Results:

No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (
P
=4.5×10
−6
, false discovery rate=0.04), which was confirmed in MEGASTROKE (
P
=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (
P
<0.001):
TAS2R20
,
TAS2R50
, and
ITPR3
. In
TAS2R50
, rs1376251 is the top SNP and has been associated with myocardial infarction by others. In
ITPR3
, a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and
ITPR3
itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (
P
<0.05).

Conclusions:

Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.
Higher Doses Improve Walking Recovery During Stroke Inpatient Rehabilitation
Authors: Klassen Tara D. , Dukelow Sean P. , Bayley Mark T. , Benavente Oscar , Hill Michael D. , Krassioukov Andrei , Liu-Ambrose Teresa , Pooyania Sepideh , Poulin Marc J. , Schneeberg Amy , Yao Jennifer , Eng Janice J.
Published: August 2020

Background and Purpose:

We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke.

Methods:

This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed.

Results:

Both DOSE1 (mean change 61 m [95% CI, 9–113],
P
=0.02) and DOSE2 (mean change 58 m, 6–110,
P
=0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care.

Conclusions:

This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01915368.
Twenty-Year Time Trends in Long-Term Case-Fatality and Recurrence Rates After Ischemic Stroke Stratified by Etiology
Authors: Rücker Viktoria , Heuschmann Peter U. , O’Flaherty Martin , Weingärtner Michael , Hess Manuela , Sedlak Claudia , Schwab Stefan , Kolominsky-Rabas Peter L.
Published: August 2020

Background and Purpose:

Data on long-term survival and recurrence after stroke are lacking. We investigated time trends in ischemic stroke case-fatality and recurrence rates over 20-years stratified by etiological subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification within a population-based stroke register in Germany.

Methods:

Data was collected within the Erlangen Stroke Project, a prospective, population-based stroke register covering a source population of 105 164 inhabitants (2010). Case fatality and recurrence rates for 3 months, 1 year, and 5 years were estimated with Kaplan-Meier estimates. Sex-specific time trends for case-fatality and recurrence rates were estimated with Cox regression. We adjusted for age, sex, and year of event and stratified for etiological subtypes. A sensitivity analysis with competing risk analysis for time trends in recurrence were performed.

Results:

Between 1996 and 2015, 3346 patients with first ischemic stroke were included; age-standardized incidence per 100 000 was 75.8 in women and 131.6 in men (2015). Overall, 5-year survival probabilities were 50.4% (95% CI, 47.9–53.1) in women and 59.2% (95% CI, 56.4–62.0) in men; 5-year survival was highest in patients with first stroke due to small-artery occlusion (women, 71.8% [95% CI, 67.1–76.9]; men, 75.9% [95% CI, 71.3–80.9]) and lowest in cardioembolic stroke (women, 35.7% [95% CI, 31.0–41.1]; men, 47.8% [95% CI, 42.2–54.3]). Five-year recurrence rates were 20.1% (95% CI, 17.5–22.6) in women and 20.1% (95% CI, 17.5–22.7) in men; 5-year recurrence rate was lowest in women in stroke due to small artery occlusion 16.0% (95% CI, 11.7–20.1) and in men in large-artery atherosclerosis 16.6% (95% CI, 8.7–23.9); highest risk of recurrence was observed in undefined strokes (women, 22.3% [95% CI, 17.8–26.6]; men, 21.4% [95% CI, 16.7–25.9]). Cox regression revealed improvements in case-fatality rates over time with differences in stroke causes. No time trends in recurrence rates were observed.

Conclusions:

Long-term survival and recurrence varied substantially by first stroke cause. Survival probabilities improved over the past 2 decades; no major trends in stroke recurrence rates were observed.
Etiological Subtypes of Transient Ischemic Attack and Ischemic Stroke in Chronic Kidney Disease
Authors: Kelly Dearbhla M. , Li Linxin , Rothwell Peter M. ,   on behalf of the Oxford Vascular Study
Published: August 2020

Background and Purpose:

Chronic kidney disease (CKD) is strongly associated with stroke risk, but the mechanisms underlying this association are unclear and might be informed by subtype-specific analyses. However, few studies have reported stroke subtypes in CKD according to established classification systems, such as the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. We, therefore, aimed to determine which transient ischemic attack and ischemic stroke subtypes using the TOAST classification occur most frequently in patients with CKD.

Methods:

In a population-based study of all transient ischemic attack and stroke (OXVASC [Oxford Vascular Study]; 2002–2017), all ischemic events were classified by TOAST subtypes (cardioembolism, large artery disease, small vessel disease, undetermined, multiple, other etiology, or incompletely investigated). Logistic regression was used to determine the relationship between CKD (defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2) and transient ischemic attack/stroke subtypes adjusted for age, sex, and hypertension and then stratified by age and estimated glomerular filtration rate category.

Results:

Among 3178 patients with transient ischemic attack (n=1167), ischemic stroke (n=1802), and intracerebral hemorrhage (n=209), 1267 (40%) had CKD. Although there was a greater prevalence of cardioembolic events (31.8% versus 21.2%;
P
<0.001) in patients with CKD, this association was lost after adjustment for age, sex, and hypertension (adjusted odds ratio=1.20 [95% CI, 0.99–1.45];
P
=0.07). Similarly, although patients with CKD had a lower prevalence of small vessel disease (8.8% versus 13.6%;
P
<0.001), undetermined (26.1% versus 39.4%;
P
<0.001), and other etiology (1.0% versus 3.6%;
P
<0.001) subtypes, these associations were also lost after adjustment (adjusted odds ratio=0.86 [0.65–1.13];
P
=0.27 and 0.73 [0.36–1.43];
P
=0.37 for small vessel disease and other defined etiology, respectively) for all but undetermined (adjusted odds ratio=0.81 [0.67–0.98];
P
=0.03).

Conclusions:

There were no independent positive associations between CKD and specific TOAST subtypes, which suggest that renal-specific risk factors are unlikely to play an important role in the etiology of particular subtypes. Future studies of stroke and CKD should report subtype-specific analyses to gain further insights into potential mechanisms.