Journal articles on the topic 'Limited label availability'
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Maiti, A., S. J. Oude Elberink, and G. Vosselman. "EFFECT OF LABEL NOISE IN SEMANTIC SEGMENTATION OF HIGH RESOLUTION AERIAL IMAGES AND HEIGHT DATA." ISPRS Annals of the Photogrammetry, Remote Sensing and Spatial Information Sciences V-2-2022 (May 17, 2022): 275–82. http://dx.doi.org/10.5194/isprs-annals-v-2-2022-275-2022.
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Abstract. The performance of deep learning models in semantic segmentation is dependent on the availability of a large amount of labeled data. However, the influence of label noise, in the form of incorrect annotations, on the performance is significant and mostly ignored. This is a big concern in remote sensing applications, wherein acquired datasets are spatially limited, labeling is done by domain experts with possible sources of high inter-and intra-observer variability leading to erroneous predictions. In this paper, we first simulate the label noise while conducting experiments on two different datasets with very high-resolution aerial images, height data, and inaccurate labels, responsible for the training of deep learning models. We then focus on the effect of these noises on the model performance. Different classes respond differently to the label noise. The typical size of an object belonging to a class is a crucial factor regarding the class-specific performance of the model trained with erroneous labels. Errors caused by relative shifts of labels are the most influential label errors. The model is generally more tolerant of the random label noise than other label errors. It has been observed that the accuracy gets reduced by at least 3% while 5% of label pixels are erroneous. In this regard, our study provides a new perspective of evaluating and quantifying the propagation of label noise in the model performance that is indeed important for adopting reliable semantic segmentation practices.
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Hu, Han, Yang Lei, Daisy Xin, Viktor Shkolnikov, Steven Barcelo, Jan Allebach, and Edward J. Delp. "2D Label Free Microscopy Imaging Analysis Using Machine Learning." Electronic Imaging 2020, no. 14 (January 26, 2020): 341–1. http://dx.doi.org/10.2352/issn.2470-1173.2020.14.coimg-341.
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Separation and isolation of living cells plays an important role in the fields of medicine and biology with label-free imaging often used for isolating cells. The analysis of label-free cell images has many challenges when examining the behavior of cells. This paper presents methods to analyze label-free cells. Many of the tools we describe are based on machine learning approaches. We also investigate ways of augmenting limited availability of training data. Our results demonstrate that our proposed methods are capable of successfully segmenting and classifying label-free cells.
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Id, Ibnu Daqiqil, Pardomuan Robinson Sihombing, and Supratman Zakir. "Handling concept drifts and limited label problems using semi-supervised combine-merge Gaussian mixture model." Bulletin of Electrical Engineering and Informatics 10, no. 6 (December 1, 2021): 3361–68. http://dx.doi.org/10.11591/eei.v10i6.3259.
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When predicting data streams, changes in data distribution may decrease model accuracy over time, thereby making the model obsolete. This phenomenon is known as concept drift. Detecting concept drifts and then adapting to them are critical operations to maintain model performance. However, model adaptation can only be made if labeled data is available. Labeling data is both costly and time-consuming because it has to be done by humans. Only part of the data can be labeled in the data stream because the data size is massive and appears at high speed. To solve these problems simultaneously, we apply a technique to update the model by employing both labeled and unlabeled instances to do so. The experiment results show that our proposed method can adapt to the concept drift with pseudo-labels and maintain its accuracy even though label availability is drastically reduced from 95% to 5%. The proposed method also has the highest overall accuracy and outperforms other methods in 5 of 10 datasets.
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Ding, Chen, Yu Li, Yue Wen, Mengmeng Zheng, Lei Zhang, Wei Wei, and Yanning Zhang. "Boosting Few-Shot Hyperspectral Image Classification Using Pseudo-Label Learning." Remote Sensing 13, no. 17 (September 6, 2021): 3539. http://dx.doi.org/10.3390/rs13173539.
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Deep neural networks have underpinned much of the recent progress in the field of hyperspectral image (HSI) classification owing to their powerful ability to learn discriminative features. However, training a deep neural network often requires the availability of a large number of labeled samples to mitigate over-fitting, and these labeled samples are not always available in practical applications. To adapt the deep neural network-based HSI classification approach to cases in which only a very limited number of labeled samples (i.e., few or even only one labeled sample) are provided, we propose a novel few-shot deep learning framework for HSI classification. In order to mitigate over-fitting, the framework borrows supervision from an auxiliary set of unlabeled samples with soft pseudo-labels to assist the training of the feature extractor on few labeled samples. By considering each labeled sample as a reference agent, the soft pseudo-label is assigned by computing the distances between the unlabeled sample and all agents. To demonstrate the effectiveness of the proposed method, we evaluate it on three benchmark HSI classification datasets. The results indicate that our method achieves better performance relative to existing competitors in few-shot and one-shot settings.
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Roth, Myron. "The availability and use of chemotherapeutic sea lice control products." Contributions to Zoology 69, no. 1-2 (2000): 109–18. http://dx.doi.org/10.1163/18759866-0690102012.
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An international survey revealed that eleven compounds representing five pesticide types are currently being used on commercial salmon farms for sea lice control. These include two organophosphates (dichlorvos and azamethiphos); three pyrethrin/pyrethroid compounds (pyrethrum, cypermethrin, deltamethrin); one oxidizing agent (hydrogen peroxide); three avermectins (ivermectin, emamectin and doramectin) and two benzoylphenyl ureas (teflubenzuron and diflubenzuron). The number of compounds available in any one country is highly variable, ranging from 9 (Norway) to 6 (Chile, United Kingdom) to 4 (Ireland, Faeroes, Canada) to 2 (US)). Dichlorvos, Azamethiphos and cypermethrin were the most widely used compounds (5 countries) followed by, hydrogen peroxide, ivermectin and emamectin (4 countries each), teflubenzuron (3 countries), diflubenzuron (2 countries), and deltamethrin, pyrethrum and doramectin (1 country each). Although, like trichlorfon, dichlorvos use is being discontinued in several countries notably Norway and the Faeroes. In most instances the availability of sea lice chemotherapeutants is limited, many being used under extra-label veterinary prescription or exemption, and special investigation permits. Access to a broad range of compounds with different modes of action, as well as application methods, has only recently been acquired making assessment of chemotherapy, and therefore integrated pest management, difficult.
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Fishman, Michael A., Ashley Scherer, Jacob Topfer, and Philip S. H. Kim. "Limited Access to On-Label Formulations of Buprenorphine for Chronic Pain as Compared with Conventional Opioids." Pain Medicine 21, no. 5 (November 7, 2019): 1005–9. http://dx.doi.org/10.1093/pm/pnz197.
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Abstract Importance Buprenorphine is a Schedule III analgesic that is recommended as the firstline long-acting opioid for the treatment of chronic pain due to its ceiling effect on respiratory depression, adverse effect profile, and analgesic efficacy. However, prescription drug coverage policies commonly require that patients try and fail multiple Schedule II conventional opioids before approval of on-label use of buprenorphine for chronic pain. Design A retrospective review was performed looking at coverage of buprenorphine in the forms of Butrans and Belbuca. Patient denial letters, web searches of insurance and pharmacy benefit managers (PBMs), and an online tool (formularylookup.com) were used to assess the coverage and availability of buprenorphine for chronic pain. Results Unrestricted access to Butrans was reported for 42% of commercial lives and 11% of Medicare lives in all locations. Unrestricted access to Belbuca was reported for 53% of commercial lives and 23% of Medicare lives in all locations. Oxycodone immediate-release has unrestricted access for 84% of commercial plans and 97% of Medicare plans. Morphine extended-release has unrestricted access for 62% of commercial lives and 65% of Medicare lives. Conclusions and Relevance There are >17,000 prescription opioid–involved deaths each year in the United States. By substituting buprenorphine as the firstline treatment for chronic and even acute pain, there may be fewer prescribed conventional opioids in the United States. Schedule III buprenorphine formulations for chronic pain should be given unrestricted access for appropriate patients before considering a Schedule II opioid as a public health priority.
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Rehmani, Muhammad Asif Ali, Saad Aslam, Shafiqur Rahman Tito, Snjezana Soltic, Pieter Nieuwoudt, Neel Pandey, and Mollah Daud Ahmed. "Power Profile and Thresholding Assisted Multi-Label NILM Classification." Energies 14, no. 22 (November 14, 2021): 7609. http://dx.doi.org/10.3390/en14227609.
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Next-generation power systems aim at optimizing the energy consumption of household appliances by utilising computationally intelligent techniques, referred to as load monitoring. Non-intrusive load monitoring (NILM) is considered to be one of the most cost-effective methods for load classification. The objective is to segregate the energy consumption of individual appliances from their aggregated energy consumption. The extracted energy consumption of individual devices can then be used to achieve demand-side management and energy saving through optimal load management strategies. Machine learning (ML) has been popularly used to solve many complex problems including NILM. With the availability of the energy consumption datasets, various ML algorithms have been effectively trained and tested. However, most of the current methodologies for NILM employ neural networks only for a limited operational output level of appliances and their combinations (i.e., only for a small number of classes). On the contrary, this work depicts a more practical scenario where over a hundred different combinations were considered and labelled for the training and testing of various machine learning algorithms. Moreover, two novel concepts—i.e., thresholding/occurrence per million (OPM) along with power windowing—were utilised, which significantly improved the performance of the trained algorithms. All the trained algorithms were thoroughly evaluated using various performance parameters. The results shown demonstrate the effectiveness of thresholding and OPM concepts in classifying concurrently operating appliances using ML.
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Kopp, Lisa M., Kathylynn Saboda, Bhuvana Setty, Mary Frances Wedekind, Daniel Weiser, Leya Schwartz, Michael Isakoff, Douglas James Harrison, Jonathan Benjamin Gill, and Pooja Hingorani. "Off label targeted therapy use in adolescents and young adults with sarcoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e21504-e21504. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e21504.
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e21504 Background: Outcomes for patients with metastatic or recurrent sarcomas remains dismal with < 20% overall survival. Due to the rarity of sarcomas, the development, testing, and approval of new therapies takes years. Most early phase clinical trials are restricted to adults leaving young patients with limited options. Little is known about the prevalence and clinical characteristics of patients receiving off-label targeted therapy (OLTT). In this multi-institutional retrospective review we evaluated OLTT use in this population. Methods: Patients with recurrent sarcoma diagnosed between the years of 2008 – 2016 were identified at six institutions. Charts were reviewed for OLTT use and additional clinical characteristics. ANOVA [Analysis of Variance] and Kruskal Wallis Rank sum tests were used for normally and non-normally distributed continuous data. Categorical data was analyzed using chi-squared tests or fisher exact tests. Results: The prevalence of OLTT use was 29% for the patients included in our analysis. Of the 99 cases, the mean age for OLTT was 18 years, ranging 3 – 34 years. Nearly half had recurrent tumor in multiple sites at the time of OLTT use, and 64% did not undergo resection prior to OLTT. Lack of clinical trial availability was the most common reason for OLTT use (31% of cases). The most common OLTT drug class used were tyrosine kinase inhibitors. Progression in 81% of cases was the primary reason for stopping OLTT and toxicity limited use in 12% of cases. One case had a complete response, 5 cases had a partial response and 4 cases had stable disease per RECIST. Conclusions: OLTT use is exceedingly prevalent in patients with recurrent sarcoma. Clinical trials for children and adolescents with recurrent sarcoma will identify optimal agents to improve outcomes in this understudied population.
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San Giovanni, Christine B., Brooke Sweeney, Joseph A. Skelton, Megan M. Kelsey, and Aaron S. Kelly. "Aversion to Off-label Prescribing in Clinical Pediatric Weight Management: The Quintessential Double Standard." Journal of Clinical Endocrinology & Metabolism 106, no. 7 (April 26, 2021): 2103–13. http://dx.doi.org/10.1210/clinem/dgab276.
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Abstract Context Pediatric obesity is now recognized as a chronic disease; yet few treatment options exist besides lifestyle modification therapy and bariatric surgery. We describe the limited availability of United States Food and Drug Administration (FDA)–approved antiobesity medications for adolescents and compare this to what is available for adults. We offer a rationale for off-label prescribing to assist with lifestyle modification therapy. We also highlight the need for more pharmacotherapy options and additional research into novel treatments for pediatric obesity. Case Description We describe a patient who is struggling with managing her weight and starting to develop complications of obesity. We offer a framework in which off-label prescribing may be beneficial to patients who have been engaging in lifestyle modification therapy yet fail to see improvement. Conclusion Lifestyle modification therapy is necessary but often insufficient in stimulating clinically meaningful weight loss when used alone in children and adolescents who struggle with weight management. Until more FDA-approved antiobesity medications are available, pediatricians may be able to help more patients achieve weight reduction goals by familiarizing themselves with the responsible use of off-label medications and implementing these tools to improve clinical outcomes. There is a critical need for more pharmacotherapy options to help pediatric patients in managing their weight and preventing or improving the insidious complications resulting from untreated obesity.
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Kim, R. B. "A multi-attribute model of Japanese consumer's purchase intention for GM foods." Agricultural Economics (Zemědělská ekonomika) 56, No. 10 (November 8, 2010): 449–59. http://dx.doi.org/10.17221/113/2009-agricecon.
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This study illustrates that consumers' GM food purchase decision is determined by a set of correlated variables. The interrelationship among the GM food purchase decision determinants is examined conceptually and empirically with a multi-attribute model, describing this interrelationship. Consumers' attitudes toward subjects such as innovation, science & technology as well as their trust towards the government's regulatory system of food safety and GM food are strong indicators of the consumers' GM food purchase decision. Given the limited availability of GM foods in the market which leads to a lack of understanding and experience of GM foods, consumers' knowledge and their search for information on food label appear to be weaker determinants of the GM food purchase decision for consumers.
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Ma, Zhen, José J. M. Machado, and João Manuel R. S. Tavares. "Weakly Supervised Video Anomaly Detection Based on 3D Convolution and LSTM." Sensors 21, no. 22 (November 12, 2021): 7508. http://dx.doi.org/10.3390/s21227508.
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Weakly supervised video anomaly detection is a recent focus of computer vision research thanks to the availability of large-scale weakly supervised video datasets. However, most existing research works are limited to the frame-level classification with emphasis on finding the presence of specific objects or activities. In this article, a new neural network architecture is proposed to efficiently extract the prominent features for detecting whether a video contains anomalies. A video is treated as an integral input and the detection follows the procedure of video-label assignment. The extraction of spatial and temporal features is carried out by three-dimensional convolutions, and then their relationship is further modeled using an LSTM network. The concise structure of the proposed method enables high computational efficiency, and extensive experiments demonstrate its effectiveness.
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Lisi, Donna M. "Specific Prescribing Information for Geriatric Use in the 2019 Product Labeling for Novel New Drug Approvals." Senior Care Pharmacist 36, no. 9 (September 1, 2021): 455–65. http://dx.doi.org/10.4140/tcp.n.2021.455.
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Objectives To review the availability of information specific to older people in the product labeling for novel US Food and Drug Administration drug approvals in 2019. Design Descriptive report. Methods Product labeling for the 48 novel new drugs approved by the US Food and Drug Administration in 2019 were analyzed for the presence of information specific to older people. The “Geriatric Use” section, Section 8.5 in the product labeling, was categorized based on the information available. Each product label was further searched using the terms “geriatric,” “elderly,” “old,” and “year.” Searches of the term “old” and “year” focused on information that mentioned adults 65 years of age or older. The sections of the product label that contained additional information related to older people was identified. Results Information was available in the “Geriatric Use” section (Section 8.5) for 46 of the 48 novel new drugs approved in 2019; 2 did not include a “Geriatric Use” section. Four product labels indicated that the drugs were not used in older people. One of the 2 medications whose labeling omitted the “Geriatric Use” section was also not indicated for use in older people. These labels were excluded from analysis.Of the remaining 42 drugs, there was insufficient numbers of patients 65 years of age and older to determine whether older patients responded differently than younger patients for 18 medications. Labeling for 15 medications indicated that there was no difference in safety and/or efficacy between younger and older persons. Product information for 6 medications indicated that the incidence of adverse events was higher for older people. The product label for 2 medications indicated that no dosage adjustment was required in older patients. One medication’s product labeling indicated that there were insufficient numbers of patients 65 years of age or older for 1 indication but that there was no difference in safety and/or efficacy for the medication’s second indication. Additional sections that referred to people 65 years of age and older included warnings and precautions, clinical trial experience, pharmacokinetics for special populations, and clinical studies. The “Geriatric Use” section of 1 product label referred to the dosage recommendations in patients with renal impairment. Conclusion Despite efforts to increase the enrollment of older people in clinical trials, 43% of the novel new drugs approved in 2019 lacked information on differences in response between older and younger populations because of insufficient numbers of study subjects. This paucity of information translates into therapeutic uncertainty regarding the safety and efficacy of these new medications in older people. An additional concern is that 14% of novel new drug labels indicated that older people are at greater risk for adverse events. Limited information specific to older people is available in other parts of the product labeling. More useful information related to older persons needs to be included in new drug labeling.
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Zhou, Jian-Peng, Lei Chen, Tianyun Wang, and Min Liu. "iATC-FRAKEL: a simple multi-label web server for recognizing anatomical therapeutic chemical classes of drugs with their fingerprints only." Bioinformatics 36, no. 11 (March 10, 2020): 3568–69. http://dx.doi.org/10.1093/bioinformatics/btaa166.
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Abstract Motivation Anatomical therapeutic chemical (ATC) classification system is very important for drug utilization and studies. Correct prediction of the 14 classes in the first level for given drugs is an essential problem for the study on such system. Several multi-label classifiers have been proposed in this regard. However, only two of them provided the web servers and their performance was not very high. On the other hand, although some rest classifiers can provide better performance, they were built based on some prior knowledge on drugs, such as information of chemical–chemical interaction and chemical ontology, leading to limited applications. Furthermore, provided codes of these classifiers are almost inaccessible for pharmacologists. Results In this study, we built a simple web server, namely iATC-FRAKEL. This web server only required the SMILES format of drugs as input and extracted their fingerprints for making prediction. The performance of the iATC-FRAKEL was much higher than all existing web servers and was comparable to the best multi-label classifier but had much wider applications. Such web server can be visited at http://cie.shmtu.edu.cn/iatc/index. Availability and implementation The web server is available at http://cie.shmtu.edu.cn/iatc/index. Contact chen_lei1@163.com Supplementary information Supplementary data are available at Bioinformatics online.
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Ouassit, Youssef, Soufiane Ardchir, Mohammed Yassine El Ghoumari, and Mohamed Azouazi. "A Brief Survey on Weakly Supervised Semantic Segmentation." International Journal of Online and Biomedical Engineering (iJOE) 18, no. 10 (July 26, 2022): 83–113. http://dx.doi.org/10.3991/ijoe.v18i10.31531.
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Semantic Segmentation is the process of assigning a label to every pixel in the image that share same semantic properties and stays a challenging task in computer vision. In recent years, and due to the large availability of training data the performance of semantic segmentation has been greatly improved by using deep learning techniques. A large number of novel methods have been proposed. However, in some crucial fields we can't assure sufficient data to learn a deep model and achieves high accuracy. This paper aims to provide a brief survey of research efforts on deep-learning-based semantic segmentation methods on limited labeled data and focus our survey on weakly-supervised methods. This survey is expected to familiarize readers with the progress and challenges of weakly supervised semantic segmentation research in the deep learning era and present several valuable growing research points in this field.
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Coggan, Andrew R. "Use of stable isotopes to study carbohydrate and fat metabolism at the whole-body level." Proceedings of the Nutrition Society 58, no. 4 (November 1999): 953–61. http://dx.doi.org/10.1017/s0029665199001263.
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The present review discusses the advantages and limitations of using stable-isotope tracers to assess carbohydrate and fat metabolism at the whole-body level. One advantage of stable-(v. radioactive-) isotope tracers is the relative ease with which the location of a label within a molecule can be determined using selected-ion-monitoring GC-mass spectrometry (SIM-GC- MS). This technique minimizes potential problems due to label recycling, allows the use of multiple-labelled compounds simultaneously (e.g. to quantify glucose cycling), and perhaps most importantly, has led to the development of unique stable-isotope methods for, for example, quantifying gluconeogenesis. However, the limited sensitivity of SIM-GC-MS sometimes requires that relatively large amounts of a stable-isotope tracer be used, thus increasing cost and potentially altering metabolism. At least theoretically, stable- (or radioactive-) isotope tracers can also be used in conjunction with indirect calorimetry to estimate utilization of muscle glycogen or triacylglycerol stores, thus potentially circumventing the need to obtain muscle biopsies. These calculations, however, require certain critical assumptions, which if incorrect could lead to major errors in the values obtained. Despite such limitations, stable-isotope tracers provide a powerful and sometimes unique tool for investigating carbohydrate and fat metabolism at the whole-body level. With continuing advances in availability, instrumentation and methods, it is likely that stable-isotope tracers will become increasingly important in the immediate future.
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Bernardo-Seisdedos, Ganeko, Jorge M. Charco, Itxaso SanJuan, Sandra García-Martínez, Pedro Urquiza, Hasier Eraña, Joaquín Castilla, and Oscar Millet. "Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria." Journal of Personalized Medicine 11, no. 6 (May 28, 2021): 485. http://dx.doi.org/10.3390/jpm11060485.
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Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.
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Iancu, Bogdan, Valentin Soloviev, Luca Zelioli, and Johan Lilius. "ABOships—An Inshore and Offshore Maritime Vessel Detection Dataset with Precise Annotations." Remote Sensing 13, no. 5 (March 5, 2021): 988. http://dx.doi.org/10.3390/rs13050988.
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Availability of domain-specific datasets is an essential problem in object detection. Datasets of inshore and offshore maritime vessels are no exception, with a limited number of studies addressing maritime vessel detection on such datasets. For that reason, we collected a dataset consisting of images of maritime vessels taking into account different factors: background variation, atmospheric conditions, illumination, visible proportion, occlusion and scale variation. Vessel instances (including nine types of vessels), seamarks and miscellaneous floaters were precisely annotated: we employed a first round of labelling and we subsequently used the CSRT tracker to trace inconsistencies and relabel inadequate label instances. Moreover, we evaluated the out-of-the-box performance of four prevalent object detection algorithms (Faster R-CNN, R-FCN, SSD and EfficientDet). The algorithms were previously trained on the Microsoft COCO dataset. We compared their accuracy based on feature extractor and object size. Our experiments showed that Faster R-CNN with Inception-Resnet v2 outperforms the other algorithms, except in the large object category where EfficientDet surpasses the latter.
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Chamnanchanunt, Supat, and Ponlapat Rojnuckarin. "Direct oral anticoagulants and travel-related venous thromboembolism." Open Medicine 13, no. 1 (November 27, 2018): 575–82. http://dx.doi.org/10.1515/med-2018-0085.
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AbstractTravel- related thromboembolism reflects the relationship between venous thromboembolism (VTE) and long-haul flights. Although this condition is rare, it may cause significant morbidity and mortality. Therefore, travelers should be evaluated for the risks for thrombosis. Travel physicians should employ a clinical risk score and select in vestigations, prophylaxis, and treatment that are appropriate for each individual. This review summarizes current VTE clinical risk scores and patient management from various reliable guidelines. We summarized 16 reliable publications for reviewing data. Direct oral anticoagulants (DOACs) are currently the standard treatment for VTE and a prophylactic measure for VTE in orthopedic surgery. Compared with a vitamin K antagonist (VKA), DOACs show better safety and similar efficacy without the need for monitoring, and have fewer food/drug interactions. Inferred from the data on general VTE, DOACs may be used to treat travel-related VTE. Although the data are lacking, DOACs may be used off-label as VTE prophylax is. Before using DOACs, physicians must know the pharmacology of the drugs well and should realize that the availability of antidotes for bleeding complications is limited.
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See, Aaron Raymond, and Welsey Daniel Advincula. "Creating Tactile Educational Materials for the Visually Impaired and Blind Students Using AI Cloud Computing." Applied Sciences 11, no. 16 (August 17, 2021): 7552. http://dx.doi.org/10.3390/app11167552.
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There are 24.5 million visually impaired and blind (VIB) students who have limited access to educational materials due to cost or availability. Although advancement in technology is prevalent, providing individualized learning using technology remains a challenge without the proper tools or experience. The TacPic system was developed as an online platform to create tactile educational materials (TEM) based on the image inputs of users who do not have prior experience in tactile photo development or 3D printing. The TacPic system allows the users to simply upload images to a website and uses AI cloud computing on the Amazon Web Services platform. First, it segments and labels the images. Then, the text label is converted into braille words. Subsequently, surface rendering and consolidation of the image and text is performed, before it is converted into a single file that is ready for 3D printing. Currently, the types of TEM that can be created are tactile flashcards, tactile maps, and tactile peg puzzles, which can be developed within a few hours. This is in contrast to a development period of weeks using traditional methods. Furthermore, the tactile educational materials were tested by two VIB teachers and six VIB students. It was found that those who are congenitally blind need more time to identify the object and rely more on the braille labels compared to students who became blind at a later age. Teachers also suggested producing TEM that use simpler images, and TEM that are suitable for both sighted and VIB students. In conclusion, the researchers successfully developed a platform that allows more educators or parents to develop personalized and individualized TEM. In the future, further optimization of the algorithms to improve segmentation and the inclusion of other features, such as color, could be undertaken. Finally, new printing materials and methods are needed to improve printing efficiency.
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Ryazanov, Igor, Amanda T. Nylund, Debabrota Basu, Ida-Maja Hassellöv, and Alexander Schliep. "Deep Learning for Deep Waters: An Expert-in-the-Loop Machine Learning Framework for Marine Sciences." Journal of Marine Science and Engineering 9, no. 2 (February 7, 2021): 169. http://dx.doi.org/10.3390/jmse9020169.
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Driven by the unprecedented availability of data, machine learning has become a pervasive and transformative technology across industry and science. Its importance to marine science has been codified as one goal of the UN Ocean Decade. While increasing amounts of, for example, acoustic marine data are collected for research and monitoring purposes, and machine learning methods can achieve automatic processing and analysis of acoustic data, they require large training datasets annotated or labelled by experts. Consequently, addressing the relative scarcity of labelled data is, besides increasing data analysis and processing capacities, one of the main thrust areas. One approach to address label scarcity is the expert-in-the-loop approach which allows analysis of limited and unbalanced data efficiently. Its advantages are demonstrated with our novel deep learning-based expert-in-the-loop framework for automatic detection of turbulent wake signatures in echo sounder data. Using machine learning algorithms, such as the one presented in this study, greatly increases the capacity to analyse large amounts of acoustic data. It would be a first step in realising the full potential of the increasing amount of acoustic data in marine sciences.
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Lefebvre, Donatien, Kevin Blanco-Valle, Jacques-Antoine Hennekinne, Stéphanie Simon, François Fenaille, François Becher, and Yacine Nia. "Multiplex Detection of 24 Staphylococcal Enterotoxins in Culture Supernatant Using Liquid Chromatography Coupled to High-Resolution Mass Spectrometry." Toxins 14, no. 4 (March 31, 2022): 249. http://dx.doi.org/10.3390/toxins14040249.
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Staphylococcal food poisoning outbreaks are caused by the ingestion of food contaminated with staphylococcal enterotoxins (SEs). Among the 27 SEs described in the literature to date, only a few can be detected using immuno-enzymatic-based methods that are strongly dependent on the availability of antibodies. Liquid chromatography, coupled to high-resolution mass spectrometry (LC-HRMS), has, therefore, been put forward as a relevant complementary method, but only for the detection of a limited number of enterotoxins. In this work, LC-HRMS was developed for the detection and quantification of 24 SEs. A database of 93 specific signature peptides and LC-HRMS parameters was optimized using sequences from 24 SEs, including their 162 variants. A label-free quantification protocol was established to overcome the absence of calibration standards. The LC-HRMS method showed high performance in terms of specificity, sensitivity, and accuracy when applied to 49 enterotoxin-producing strains. SE concentrations measured depended on both SE type and the coagulase-positive staphylococci (CPS) strain. This study indicates that LC-MS is a relevant alternative and complementary tool to ELISA methods. The advantages of LC-MS clearly lie in both the multiplex analysis of a large number of SEs, and the automated analysis of a high number of samples.
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Tomanic, Dragana, Zorana Kovacevic, Dragica Stojanovic, Branislava Belic, Nenad Stojanac, Ivan Stancic, and Ivan Galic. "Metronidazole in the prophylaxis and treatment of dogs and cats." Zbornik Matice srpske za prirodne nauke, no. 141 (2021): 95–105. http://dx.doi.org/10.2298/zmspn2141095t.
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Ever since their discovery, antimicrobials have helped in controlling and treating infections in both humans and animals. The control of infectious diseases is endangered by the rise of microorganisms that are resistant to this group of drugs. Limited availability of authorized veterinary drugs leads to prescription of human approved drugs. The aim of our study was to describe metronidazole use patterns and its accordance with scientific literature in Serbia. Results have shown that majority of prescriptions were written to dogs, while 27.1% prescriptions were for cats. Most common general conditions were dental and digestive disorders. Our study shows that metronidazole is available in oral and injectable form, while cats were only treated with injectable formulation. Even though pre?scription of human approved drugs for companion animals is allowed by Law, there is no official record of data on the extent or nature of off-label use in Serbia. Such information is essential for guiding antimicrobial use policy in small animal veterinary practice as well as for assessing the risk of transmission of antimicrobial resistance to humans. Recognizing the importance of antimicrobial resistance and ensuring more judicious use of antibiotics are key elements to any strategy for maintaining the usefulness of antimicrobial drugs in animals and humans.
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Moore, Finola E., Elaine G. Garcia, Riadh Lobbardi, Esha Jain, Qin Tang, John C. Moore, Mauricio Cortes, et al. "Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish." Journal of Experimental Medicine 213, no. 6 (May 2, 2016): 979–92. http://dx.doi.org/10.1084/jem.20152013.
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Hematopoiesis culminates in the production of functionally heterogeneous blood cell types. In zebrafish, the lack of cell surface antibodies has compelled researchers to use fluorescent transgenic reporter lines to label specific blood cell fractions. However, these approaches are limited by the availability of transgenic lines and fluorescent protein combinations that can be distinguished. Here, we have transcriptionally profiled single hematopoietic cells from zebrafish to define erythroid, myeloid, B, and T cell lineages. We also used our approach to identify hematopoietic stem and progenitor cells and a novel NK-lysin 4+ cell type, representing a putative cytotoxic T/NK cell. Our platform also quantified hematopoietic defects in rag2E450fs mutant fish and showed that these fish have reduced T cells with a subsequent expansion of NK-lysin 4+ cells and myeloid cells. These data suggest compensatory regulation of the innate immune system in rag2E450fs mutant zebrafish. Finally, analysis of Myc-induced T cell acute lymphoblastic leukemia showed that cells are arrested at the CD4+/CD8+ cortical thymocyte stage and that a subset of leukemia cells inappropriately reexpress stem cell genes, including bmi1 and cmyb. In total, our experiments provide new tools and biological insights into single-cell heterogeneity found in zebrafish blood and leukemia.
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Saunthararajah, Yogenthiran, Robert Molokie, Seema Sidhwani, Santosh Saraf, Stephen Vara, Michel Gowhari, and Joseph DeSimone. "Decitabine Improves Clinical Outcomes in Severely Ill Sickle Cell Disease Patients Who Have Exhausted Standard of Care Options." Blood 110, no. 11 (November 16, 2007): 3792. http://dx.doi.org/10.1182/blood.v110.11.3792.3792.
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Abstract Interventions such as immunization, penicillin prophylaxis, hydroxyurea and transfusion have extended life in patients with sickle cell disease (SCD). Nonetheless, these interventions are limited by toxicity or effectiveness; continued substantial morbidity and mortality in SCD indicates the need for better disease modification. In previous phase I/II clinical trials, 13 of 13 patients treated with the DNA hypomethylating agent decitabine responded with clinically significant fetal hemoglobin and total hemoglobin elevation and improvement in surrogate clinical end-points. However, in these early studies, no clinical end-points were measured and further studies have been delayed by funding issues. We describe an off-label experience in four patients with severe SCD that suggests remarkable clinical effectiveness in patients who have exhausted standard of care and are severely ill; tolerability even in the severely ill; a mechanism of action based on increased reticulocytosis in addition to increased fetal hemoglobin. All four patients had multiple alloantibodies and red-cell auto-antibodies that limited availability and increased risks of transfusion, and had previously been treated with hydroxyurea with continued clinical deterioration. Three of the four patients had relative reticulocytopenia (absolute reticulocyte count <250x109/L and hemoglobin <9g/dl) and were receiving erythropoietin or darbopoietin for more than 8 weeks with continued progressive anemia and progressive congestive heart failure. All four patients were ECOG performance status 3 and ineligible for available clinical trials. Based on the clinical trial experience conducted at our institution, decitabine therapy at 0.1–0.2 mg/kg 1–2X/week was initiated in these patients not for research purposes but with the intent to produce direct clinical benefit. The limited clinical data and potential for unanticipated toxicity was discussed in full with each patient and family members. IRB approval was obtained for a retrospective chart review. No decitabine related adverse events occurred. All patients demonstrated >2g/dl increases in hemoglobin levels with an associated improvement in clinical status - decrease in pain, improvement in performance status, improvement in congestive heart failure symptoms/signs. Upward trends in the platelet and reticulocyte counts concurrent with downward trends in the neutrophil counts were consistent with previously observed effects of low dose decitabine or the related compound 5-azacytidine. Clinically significant neutropenia was avoided by dose reductions that did not reverse the improved hemoglobin levels. The differentiation altering effects of low dose decitabine relieve SCD anemia by decreasing hemolysis (through elevated HbF) and increasing reticulocytosis. Previous clinical trials, and this off-label experience, suggest that decitabine holds remarkable promise as a disease modifying agent for SCD and β-thalassemia. Further clinical trials to confirm this impression should be supported.
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Gonzalez, Antonio V., Andrew J. Ullmann, Nikolaos G. Almyroudis, and Brahm H. Segal. "Broad-Spectrum Antifungal Prophylaxis in Patients With Cancer at High Risk for Invasive Mold Infections: Point." Journal of the National Comprehensive Cancer Network 6, no. 2 (February 2008): 175–82. http://dx.doi.org/10.6004/jnccn.2008.0014.
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Invasive fungal infections (IFIs) are a leading cause of infection-related mortality in patients with acute leukemia and prolonged neutropenia and in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). Although invasive candidiasis was the principal IFI predating fluconazole prophylaxis, invasive aspergillosis and other mold infections now cause most deaths from fungal infection in this patient population. The availability of broad-spectrum antifungal agents that can be safely administered over prolonged periods has stimulated interest in using mold-active prophylactic agents early as prophylaxis rather than later as therapy for suspected or documented IFIs. Two recent, prospective, randomized trials have shown a clear benefit of posaconazole prophylaxis in patients with myelodysplastic syndrome and acute mye-logenous leukemia with prolonged neutropenia and in allogeneic HSCT recipients with severe GVHD. In contrast, the peer-reviewed published database on the strategy of preemptive antifungal therapy, in which yeast-active prophylaxis (fluconazole) or no antifungal prophylaxis is used initially and modifications are triggered by a combination of laboratory markers and chest CT scans, is currently limited to an open-label feasibility study. Does sufficient evidence currently exist that the net benefit of the preemptive approach is at least on a par with posaconazole prophylaxis in the specific patient groups that were studied? The authors believe not and that more research is needed before the pre-emptive strategy can be recommended.
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Sauter, Daniel, Georg Lodde, Felix Nensa, Dirk Schadendorf, Elisabeth Livingstone, and Markus Kukuk. "Validating Automatic Concept-Based Explanations for AI-Based Digital Histopathology." Sensors 22, no. 14 (July 18, 2022): 5346. http://dx.doi.org/10.3390/s22145346.
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Digital histopathology poses several challenges such as label noise, class imbalance, limited availability of labelled data, and several latent biases to deep learning, negatively influencing transparency, reproducibility, and classification performance. In particular, biases are well known to cause poor generalization. Proposed tools from explainable artificial intelligence (XAI), bias detection, and bias discovery suffer from technical challenges, complexity, unintuitive usage, inherent biases, or a semantic gap. A promising XAI method, not studied in the context of digital histopathology is automated concept-based explanation (ACE). It automatically extracts visual concepts from image data. Our objective is to evaluate ACE’s technical validity following design science principals and to compare it to Guided Gradient-weighted Class Activation Mapping (Grad-CAM), a conventional pixel-wise explanation method. To that extent, we created and studied five convolutional neural networks (CNNs) in four different skin cancer settings. Our results demonstrate that ACE is a valid tool for gaining insights into the decision process of histopathological CNNs that can go beyond explanations from the control method. ACE validly visualized a class sampling ratio bias, measurement bias, sampling bias, and class-correlated bias. Furthermore, the complementary use with Guided Grad-CAM offers several benefits. Finally, we propose practical solutions for several technical challenges. In contradiction to results from the literature, we noticed lower intuitiveness in some dermatopathology scenarios as compared to concept-based explanations on real-world images.
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Liang, Yuzhi, Min Yang, Jia Zhu, and S. M. Yiu. "Out-domain Chinese new word detection with statistics-based character embedding." Natural Language Engineering 25, no. 2 (February 11, 2019): 239–55. http://dx.doi.org/10.1017/s1351324918000463.
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AbstractUnlike English and other Western languages, many Asian languages such as Chinese and Japanese do not delimit words by space. Word segmentation and new word detection are therefore key steps in processing these languages. Chinese word segmentation can be considered as a part-of-speech (POS)-tagging problem. We can segment corpus by assigning a label for each character which indicates the position of the character in a word (e.g., “B” for word beginning, and “E” for the end of the word, etc.). Chinese word segmentation seems to be well studied. Machine learning models such as conditional random field (CRF) and bi-directional long short-term memory (LSTM) have shown outstanding performances on this task. However, the segmentation accuracies drop significantly when applying the same approaches to out-domain cases, in which high-quality in-domain training data are not available. An example of out-domain applications is the new word detection in Chinese microblogs for which the availability of high-quality corpus is limited. In this paper, we focus on out-domain Chinese new word detection. We first design a new method Edge Likelihood (EL) for Chinese word boundary detection. Then we propose a domain-independent Chinese new word detector (DICND); each Chinese character is represented as a low-dimensional vector in the proposed framework, and segmentation-related features of the character are used as the values in the vector.
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van Berge Henegouwen, Jade Maxime, Louisa Rose Hoes, Hanneke van der Wijngaart, Daphne Liselotte Van Der Velden, Alwin Huitema, Edwin P. J. G. Cuppen, Elly J. Lugtenburg, et al. "Update on the Drug Rediscovery Protocol: Expanded use of existing anticancer drugs in patients with a known molecular profile." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS3149. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps3149.
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TPS3149 Background: With the emergence of large-scale genetic tumor profiling and the increasing availability of approved targeted therapies, precision medicine has become crucial in cancer treatment. However, for many cancers the relative contribution of either tumor type or genetic aberration to drug sensitivity often remains unknown. Since drug access is generally limited to the on-label indication and outcome of off-label use is not systematically collected in clinical practice, innovative trials facilitating drug access, whilst systematically analyzing treatment outcomes, are urgently needed. Methods: The Drug Rediscovery Protocol (DRUP) is an ongoing, prospective, non-randomized, multi-drug, and pan-cancer trial, in which patients with advanced cancer, who have exhausted all standard of care treatment options, are treated with either targeted or immunotherapy matched to their genetic tumor profile. All submitted patients are reviewed and enrolled in multiple parallel cohorts, preceded by a baseline tumor biopsy for whole genome sequencing to confirm previously identified variants and for exploratory biomarker analyses. Each cohort is defined by a study drug, histologic tumor type, and molecular tumor profile. Efficacy is analyzed per cohort: 8 patients in stage I and 16 more in stage II if ≥ 1 response is observed in the first stage. Primary endpoints include objective response rate, stable disease at 16 weeks, and grade ≥3 adverse events. Since the start of recruitment in September 2016, 870 patients have been submitted for review and 365 patients (42%) have started treatment in one of 101 opened cohorts. Eight cohorts have graduated to the second stage, two cohorts completed accrual in either their first or second stage, and one cohort was closed due to a registered indication. Twenty-two different study treatments (i.e. immunotherapy, monoclonal antibodies, and PARP/small molecule inhibitors), provided by 11 different pharmaceutical companies, are currently available in DRUP. Data sharing with similar trials such as TAPUR and CAPTUR enables to achieve completion of slow accruing cohorts and affirm conclusions. Clinical trial information: NCT02925234.
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Sandilya, Vijay, and Namita Gupta. "Use of recombinant factor VIIa in treatment of bleeding episodes for patients with refractoriness to platelet transfusion therapy." Blood 120, no. 21 (November 16, 2012): 4382. http://dx.doi.org/10.1182/blood.v120.21.4382.4382.
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Abstract Abstract 4382 Recombinant factor VIIa (rVIIa) is currently used for treatment and prevention of bleeding episodes in hemophilia with inhibitors, congenital factor VII deficiency, and acquired hemophilia. We report a series of 3 cases of immune mediated refractoriness to platelet transfusion therapy that were successfully treated with rVIIa, an off-label use. Data was obtained retrospectively over a 6 month period. All patients were known to be platelet refractory with presence of significant titers of plasma HLA antibodies. Two patients had undergone matched unrelated donor HSCT and the third patient suffered from Myelodysplastic syndrome (MDS). Two of the patients presented with GI bleeding and the third with intracranial bleeding. Due to limited availability of HLA matched platelets and negligible increment in platelet count from ABO matched platelets, use of factor VIIa was considered. Transfusion with PRBCs to maintain a Hemoglobin (Hb) > 8.0g/dl and close monitoring of coagulation parameters were performed. Patients received boluses of rFVIIa at 90mcg/kg, every 3–12 hrs. The dose of rFVIIa ranged from 10800–28,000 mcg/day. All three episodes of bleeding achieved clinical or radiologic improvement. No toxicities or arteriothrombotic events were observed with rFVIIa use. Our experience indicates that rFVIIa might be an effective treatment option for patients with refractoriness to platelet transfusion therapy. The optimal dosing schedule in this clinical situation needs to be studied. Patient demographics and outcomes Patient Diagnosis Pre-intervention Hb/platelet rFVIIa used (microgms) PRBC/Platelet transfused (units) Clinical outcome SV – GI bleed ALL-MUD, BMT, day +102. 7.9/4000 28000/d × 4 days 6/3 Bleeding stopped and Hemoglobin stabilized on day 4 CS- GI bleed AML-MUD,BMT, day + 78 7.8/3000 25200/d × 2 days 2/2 Bleeding stopped and Hemoglobin stabilized on day 2 MW-Intracranial hemorrhage MDS – IPSS risk group Intemediate-2 7.6/6000 10800/d × 2 days 2/2 Improvement in Neurological exam and stabilization on CT scan seen by day 3 Disclosures: Off Label Use: Recombinant factor VIIa for refractoriness to platelet transfusion therapy.
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Griffin, Jacqueline R., Tomi Jun, Bobby Chi-Hung Liaw, Sunny Guin, Che-Kai Tsao, Vaibhav G. Patel, Michael Rossi, et al. "Clinical utility of next-generation sequencing for prostate cancer in the context of a changing treatment landscape." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 112. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.112.
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112 Background: Next-generation sequencing (NGS) is increasingly common in clinical practice, but its clinical utility may depend on the availability of sequencing-directed therapies (SDT). There were no FDA-approved SDTs in prostate cancer (PCa) until 2020, when PARP inhibitors olaparib and rucaparib were approved for tumors bearing alterations in certain homologous recombination repair (HRR) genes. We assessed the clinical utility of NGS in PCa before and after the approval of these agents in a single academic medical center. Methods: This was a retrospective single-center study including all PCa patients seen at Mount Sinai Hospital (New York, NY) between 2018–2021 who received NGS via the 161-gene Sema4 Signal Solid Tumor Panel. Clinical data were extracted from the Mount Sinai electronic medical record using a proprietary automated pipeline with limited manual curation (Sema4 PRODB). The primary outcome was clinical utility in metastatic PCa, defined as the proportion of metastatic PCa patients who received SDT. Secondary outcomes included time-to-next-treatment (TTNT, defined as time from SDT start to the start of next systemic therapy) and the proportion of patients with clinically actionable (as of 9/2021) alterations, defined as either Tier 1 (associated with FDA-approved treatments in prostate cancer) or Tier 2 (associated with either off-label or investigational agents). Results: The cohort consisted of 332 PCa patients; 51% (N = 170) were sequenced in 2020 or later. The median age at diagnosis was 65 (IQR 12). The most advanced stage documented was localized for 39% (N = 129) and metastatic for 61% (N = 203). Overall, 167 actionable alterations were identified in 125 patients (38% of cohort). Of the actionable alterations, 31% (N = 51) were Tier 1 and 69% (N = 116) were Tier 2. Of the 44 patients with Tier 1 alterations, 8 (18%) received SDT (all received olaparib). The proportion of metastatic patients receiving olaparib increased from 1% (2/145) before 2020 to 10% (6/58) during or after 2020 (p = 0.008). Of the 36 patients not receiving olaparib: 20 were sequenced before FDA approval and were treated with an alternative systemic therapy; 8 had localized disease and were not eligible; 8 had limited follow-up or unknown treatment status. For those who received olaparib, median TTNT was 5 months. Conclusions: In this single-center retrospective cohort, clinical utility of NGS was linked to treatment landscape. Increases in NGS test volume and olaparib use coincided with the approval of PARP inhibitors for patients with HRR-mutated prostate cancers. Notably, NGS was used to match patients to off-label/ investigational olaparib before its FDA approval.[Table: see text]
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Gerlach, Jared Q., Stephen Cunningham, Marian Kane, and Lokesh Joshi. "Glycobiomimics and glycobiosensors." Biochemical Society Transactions 38, no. 5 (September 24, 2010): 1333–36. http://dx.doi.org/10.1042/bst0381333.
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Following steady advances in analytical technologies, our knowledge in glycomics is now increasing rapidly. Over the last decade, specific glycans have been described that are associated with a range of diseases, such as cancer and inflammation, with host–pathogen interactions and with various stages during stem cell development and differentiation. Simultaneously, deeper structural insight has been gained on glycosylated biopharmaceutical protein therapeutics manufactured in CHO (Chinese-hamster ovary) and other cell systems. This glycomic information is highly relevant for clinicians and biomanufacturing industries as a new class of glycobiomarkers emerges. However, current methods of glycoanalysis are primarily research tools and are not suitable for point-of-care on-site detection and analysis, or sensor devices. Lectin-based glycan detection provides the most promising approach to fill these gaps. However, the limited availability of lectins with high specificity and sensitivity for specific glycan motifs presents one of the main challenges in building reliable glycobiosensors. Recent reports have demonstrated the use of recombinant protein engineering, phage display and aptamer technologies in the production of lectin mimics, as well as the construction of biosensors that are capable of rapidly detecting glycan motifs at low levels in both a labelled and label-free manner. These are primarily proof-of-principle reports at this stage, but some of the approaches, either alone or in combination, will lead to functional glycobiosensors in the coming years which will be valuable tools for the clinical, biopharmaceutical and life science research communities.
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Benglis, David, Michael Y. Wang, and Allan D. Levi. "A Comprehensive Review of the Safety Profile of Bone Morphogenetic Protein in Spine Surgery." Operative Neurosurgery 62, suppl_5 (May 1, 2008): ONS423—ONS431. http://dx.doi.org/10.1227/01.neu.0000326030.24220.d8.
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Abstract WE REVIEW OUR current understanding of the development and potential clinical applications of bone morphogenetic protein (BMP) in spine surgery. We also review the evidence for adverse events associated with the use of BMP and suggest potential reasons for these events and means of complication avoidance. Bone morphogenetic protein 2 (rhBMP-2) is approved by the Food and Drug Administration for anterior lumbar interbody fusion; rhBMP-7, on the other hand, is approved for long bone defects and has received a humanitarian device exemption for revision posterolateral lumbar operations and recalcitrant long bone unions. Nevertheless, “off-label” use in various spinal procedures has been reported and is increasing in frequency. Specific guidelines for rhBMP-2 and rhBMP-7 use are lacking because of the limited availability of randomized controlled clinical trials and its diverse use in many spinal applications. Mechanisms of delivery, carrier type, graft position, surgical location, and variations in BMP concentration may differ from one surgery to the next. Adverse events linked to either rhBMP-2 or rhBMP-7 use include ectopic bone formation, bone resorption or remodeling at the graft site, hematoma, neck swelling, and painful seroma. Other potential theoretical concerns include carcinogenicity and teratogenic effects. In this review, we provide the reader with a historical perspective on BMP, current and past research to support its use in spinal procedures, and a critical analysis of the complications reported thus far.
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Dovala, Dustin, Christopher M. Rath, Qijun Hu, William S. Sawyer, Steven Shia, Robert A. Elling, Mark S. Knapp, and Louis E. Metzger. "Structure-guided enzymology of the lipid A acyltransferase LpxM reveals a dual activity mechanism." Proceedings of the National Academy of Sciences 113, no. 41 (September 28, 2016): E6064—E6071. http://dx.doi.org/10.1073/pnas.1610746113.
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Gram-negative bacteria possess a characteristic outer membrane, of which the lipid A constituent elicits a strong host immune response through the Toll-like receptor 4 complex, and acts as a component of the permeability barrier to prevent uptake of bactericidal compounds. Lipid A species comprise the bulk of the outer leaflet of the outer membrane and are produced through a multistep biosynthetic pathway conserved in most Gram-negative bacteria. The final steps in this pathway involve the secondary acylation of lipid A precursors. These are catalyzed by members of a superfamily of enzymes known as lysophospholipid acyltransferases (LPLATs), which are present in all domains of life and play important roles in diverse biological processes. To date, characterization of this clinically important class of enzymes has been limited by a lack of structural information and the availability of only low-throughput biochemical assays. In this work, we present the structure of the bacterial LPLAT protein LpxM, and we describe a high-throughput, label-free mass spectrometric assay to characterize acyltransferase enzymatic activity. Using our structure and assay, we identify an LPLAT thioesterase activity, and we provide experimental evidence to support an ordered-binding and “reset” mechanistic model for LpxM function. This work enables the interrogation of other bacterial acyltransferases’ structure–mechanism relationships, and the assay described herein provides a foundation for quantitatively characterizing the enzymology of any number of clinically relevant LPLAT proteins.
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Deschoenmaeker, Frédéric, Raphaël Facchini, Baptiste Leroy, Hanène Badri, C. C. Zhang, and Ruddy Wattiez. "Proteomic and cellular views of Arthrospira sp. PCC 8005 adaptation to nitrogen depletion." Microbiology 160, no. 6 (June 1, 2014): 1224–36. http://dx.doi.org/10.1099/mic.0.074641-0.
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Cyanobacteria are photosynthetic prokaryotes that play a crucial role in the Earth’s nitrogen and carbon cycles. Nitrogen availability is one of the most important factors in cyanobacterial growth. Interestingly, filamentous non-diazotrophic cyanobacteria, such as Arthrospira sp. PCC 8005, have developed survival strategies that enable them to adapt to nitrogen deprivation. Metabolic studies recently demonstrated a substantial synthesis and accumulation of glycogen derived from amino acids during nitrogen starvation. Nevertheless, the regulatory mechanism of this adaptation is poorly understood. To the best of our knowledge, this study is the first proteomic and cellular analysis of Arthrospira sp. PCC 8005 under nitrogen depletion. Label-free differential proteomic analysis indicated the global carbon and nitrogen reprogramming of the cells during nitrogen depletion as characterized by an upregulation of glycogen synthesis and the use of endogenous nitrogen sources. The degradation of proteins and cyanophycin provided endogenous nitrogen when exogenous nitrogen was limited. Moreover, formamides, cyanates and urea were also potential endogenous nitrogen sources. The transporters of some amino acids and alternative nitrogen sources such as ammonium permease 1 were induced under nitrogen depletion. Intriguingly, although Arthrospira is a non-diazotrophic cyanobacterium, we observed the upregulation of HetR and HglK proteins, which are involved in heterocyst differentiation. Moreover, after a long period without nitrate, only a few highly fluorescent cells in each trichome were observed, and they might be involved in the long-term survival mechanism of this non-diazotrophic cyanobacterium under nitrogen deprivation.
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Ginelli, Davide, Daniela Micucci, Marco Mobilio, and Paolo Napoletano. "UniMiB AAL: An Android Sensor Data Acquisition and Labeling Suite." Applied Sciences 8, no. 8 (July 31, 2018): 1265. http://dx.doi.org/10.3390/app8081265.
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In recent years, research on techniques to identify and classify activities of daily living (ADLs) has significantly grown. This is justified by the many application domains that benefit from the application of these techniques, which span from entertainment to health support. Usually, human activities are classified by analyzing signals that have been acquired from sensors. Inertial sensors are the most commonly employed, as they are not intrusive, are generally inexpensive and highly accurate, and are already available to the user because they are mounted on widely used devices such as fitness trackers, smartphones, and smartwatches. To be effective, classification techniques should be tested and trained with datasets of samples. However, the availability of publicly available datasets is limited. This implies that it is difficult to make comparative evaluations of the techniques and, in addition, that researchers are required to waste time developing ad hoc applications to sample and label data to be used for the validation of their technique. The aim of our work is to provide the scientific community with a suite of applications that eases both the acquisition of signals from sensors in a controlled environment and the labeling tasks required when building a dataset. The suite includes two Android applications that are able to adapt to both the running environment and the activities the subject wishes to execute. Because of its simplicity and the accuracy of the labeling process, our suite can increase the number of publicly available datasets.
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Akolkar, Dadasaheb B., Timothy Crook, Darshana Patil, Anantbhushan Ranade, Amit Bhatt, Sewanti Limaye, Vineet Datta, et al. "Multi-analyte interrogation based treatment of advanced refractory cancers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15624-e15624. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15624.
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e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.
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Kelley, Michael J., Jill Duffy, Bradley J. Hintze, Christina D. Williams, and Neil L. Spector. "Implementation of precision oncology in the Veterans Health Administration (VHA)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6507. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6507.
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6507 Background: VHA is the US’s largest integrated healthcare system providing care to over 6 million Veterans (~40% in rural areas). Precision Oncology offers the promise of effective, low-toxicity targeted therapies tailored to individual tumor genomics but is unequally available to patients in the US. As part of the Cancer Moonshot, VHA is implementing a system-wide Precision Oncology Program (POP) including patients in rural areas, where specialty oncology care has historically had limited availability. Methods: Patients tested with multigene NGS tumor sequencing through 1 of 2 contracted vendors were identified from POP records and cancer characteristics were extracted from POP and medical records. Drug use data was obtained from the VA Corporate Data Warehouse. NGS testing results and annotations were extracted from POP records. Results: A total of 978 tumor samples were sent for NGS testing since program inception in 2015. The most common diagnoses are lung (464: adeno 314, squamous 107), GI (87), LN (75), liver (56), H&N (52), and prostate (43). The rate of sample test requests increased rapidly after national implementation in July 2016 (mean 23 samples/month prior to implementation to mean 126 samples/month 3 months later) as did the number of participating facilities (mean 8/month to 27/month). Sequencing success rate increased from 68% to 71% over the same interval while mean turn around time remained similar at 19.7 and 19.1 d, respectively. NGS results are available for a cohort of 344 patients including: lung 200 (adeno 138, squamous 51), skin 28, LN 20, liver 19, GI 16. 979 variants were found including TP53 278, KRAS 106, STK11, APC 38, PIK3CA 38, and CDKN2A 37. 228 patients had actionable results (on-label drug 24, off-label drug 165, clinical trial 213). To date, 8 patients received a recommended drug outside a clinical trial between 11 and 288 d after testing (median 82 d); 4 additional patients had received an NGS-recommended drug prior to testing. Conclusions: Implementation of tumor NGS testing as part of Precision Oncology Program in a US distributed healthcare system is feasible. Further program implementation and provision of appropriate targeted drugs both on and off study will be necessary to impact patient outcomes.
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Sadaps, Meena, Pauline Funchain, Petros Grivas, Bassam N. Estfan, Jame Abraham, James Stevenson, Nathan A. Pennell, Alok A. Khorana, Brian James Bolwell, and Davendra Sohal. "Precision oncology experience at a tertiary care center." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e18118-e18118. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e18118.
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e18118 Background: Precision oncology – use of tumor genomic profiling to guide therapies – is widely discussed but with limited real-world data. We have previously reported our prospective study on feasibility and clinical utility of routine somatic genomic testing of solid tumors [ J Natl Cancer Inst. 2015; 108(3)], and here we report our longitudinal experience, focusing on therapeutic impact. Methods: Records were reviewed for consecutive adult patients seen at Cleveland Clinic for a solid tumor malignancy without known curative options where tumor genomic profiling was ordered using FoundationOne™ (Cambridge, MA). Results were discussed at the Cleveland Clinic Genomics Tumor Board, and therapeutic recommendations were conveyed to the primary oncologist. Data for this cohort study approved by the Cleveland Clinic IRB included subsequent therapies and clinical outcomes. Results: From 2013 to 2016, 330 patients had tumor genomic testing ordered. Median age was 61 years (range, 24-94); 170 (51.5%) were female; 289 (87.6%) were Caucasian. Colorectal (21.5%), breast (17%), lung (16.1%), and pancreatobiliary (11.5%) cancers were the most common diagnoses. In 300 resulted cases, a median of 4 (0-20) alterations per specimen were noted; the most commonly altered genes were TP53 (n = 174), KRAS (n = 75), APC (n = 65), CDKN2A/B (n = 49), and PIK3CA/ PIK3R (n = 46). A specific therapy targeting an actionable alteration was recommended in 51% (153/300) of patients, and 11.7% (n = 35) received such therapy: 14 on clinical trials, 5 on-label, and 16 off-label. Most common targets for therapy were PIK3CA/PIK3R/PTEN (n = 7), HER2 (6), BRAF (3), EGFR (3), and ALK, FLT3, NTRK1 and RET (2 each). At last follow-up, of 35 patients receiving targeted therapy, best responses were: complete response (n = 1, 2.9%), partial response (n = 5, 14.3%), stable disease (n = 14, 40%), progressive disease (n = 11, 31.4%); data not available for 4 patients. Non-availability of clinical trials was a common reason for non-receipt of targeted therapy. Conclusions: Tumor genomic profiling influenced treatment in 11.7% of patients in this cohort, and 57% of those receiving targeted therapy experienced clinical benefit. These data can help guide real-world discussions of precision oncology.
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Esfandyarpour, Rahim, Matthew J. DiDonato, Yuxin Yang, Naside Gozde Durmus, James S. Harris, and Ronald W. Davis. "Multifunctional, inexpensive, and reusable nanoparticle-printed biochip for cell manipulation and diagnosis." Proceedings of the National Academy of Sciences 114, no. 8 (February 6, 2017): E1306—E1315. http://dx.doi.org/10.1073/pnas.1621318114.
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Isolation and characterization of rare cells and molecules from a heterogeneous population is of critical importance in diagnosis of common lethal diseases such as malaria, tuberculosis, HIV, and cancer. For the developing world, point-of-care (POC) diagnostics design must account for limited funds, modest public health infrastructure, and low power availability. To address these challenges, here we integrate microfluidics, electronics, and inkjet printing to build an ultra–low-cost, rapid, and miniaturized lab-on-a-chip (LOC) platform. This platform can perform label-free and rapid single-cell capture, efficient cellular manipulation, rare-cell isolation, selective analytical separation of biological species, sorting, concentration, positioning, enumeration, and characterization. The miniaturized format allows for small sample and reagent volumes. By keeping the electronics separate from microfluidic chips, the former can be reused and device lifetime is extended. Perhaps most notably, the device manufacturing is significantly less expensive, time-consuming, and complex than traditional LOC platforms, requiring only an inkjet printer rather than skilled personnel and clean-room facilities. Production only takes 20 min (vs. up to weeks) and $0.01—an unprecedented cost in clinical diagnostics. The platform works based on intrinsic physical characteristics of biomolecules (e.g., size and polarizability). We demonstrate biomedical applications and verify cell viability in our platform, whose multiplexing and integration of numerous steps and external analyses enhance its application in the clinic, including by nonspecialists. Through its massive cost reduction and usability we anticipate that our platform will enable greater access to diagnostic facilities in developed countries as well as POC diagnostics in resource-poor and developing countries.
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Stein, Mark, Agnes Nemet, Santhosh Kumar, William Lumry, Hartwig Gajek, Roberta Macchia, Vladislava Zamfirova, et al. "Efficacy, safety, and tolerability of Kedrion 10% IVIG in primary immunodeficiency." LymphoSign Journal 3, no. 3 (September 1, 2016): 99–109. http://dx.doi.org/10.14785/lymphosign-2016-0004.
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Background: Primary immunodeficiency involving defective antibody formation requires antibody replacement therapy with immunoglobulin products to prevent and reduce infections. Immunoglobulin for intravenous use (IVIG) is a processed blood product with limited availability, and the various marketed IVIG products may have different tolerability among patients. New IVIG products are therefore necessary to offer options to patients and to reduce the risk of a product shortage. Methods: Forty-five adult and pediatric patients with primary immunodeficiency, documented agammaglobulinemia or hypogammaglobulinemia, and antibody deficiency were enrolled in a prospective, multi-centre, open-label, single-arm historically controlled Phase III study to evaluate the safety, efficacy, and pharmacokinetics of a new 10% IVIG produced by Kedrion. Results: Forty-four patients completed the study while one withdrew consent. Over the 12-month study period, only 2 episodes of acute serious bacterial infections (both bacterial pneumonias) were recorded, for a mean annual event rate of 0.04 per subject, with an upper one-sided 99% confidence limit of 0.11. Values for all secondary efficacy endpoints were comparable with those in similar studies. The primary safety endpoint was met as the rate of infusions temporally associated (i.e., within 72 hours) with ≥1 adverse event was 16% (upper 95% confidence limit 20.4%). Pharmacokinetics were assessed in 31 patients and found to be comparable with those published for other IVIG products. Conclusion: Kedrion IVIG 10% is safe, efficacious, and well tolerated by patients with primary immunodeficiency. Statement of novelty: This report describes the safety, efficacy, and pharmacokinetics of a new IVIG preparation.
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Praditsuktavorn, Banjerd, and Pornprom Muangman. "The use of artificial dermis for corrective surgery on burn scars." Asian Biomedicine 9, no. 1 (January 31, 2017): 101–6. http://dx.doi.org/10.5372/1905-7415.0805.376.
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Abstract Background Hypertrophic scarring from burn injuries on large skin areas is of great concern for both patients and attending physicians because of significant functional and cosmetic impairment. Surgery for scar corrections is challenging because of limitations on the availability of normal tissue. An alternative method for scar correction using artificial dermis is now possible. Artificial dermis can be used in the reconstruction of scars, burn injuries on large skin areas and in patients who do not have sufficient donor sites for skin grafts after scar excisions. Objective To report the efficacy of artificial dermis on a 20 years old Thai man with severe scar contracture from burn injuries. Method An open-label case study, the severe contracture case underwent scar excision and was applied with artificial dermis. Result A 20-year-old man had severe scar contractures on his left arm, forearm, and elbow, and a shearing wound with a scar at his left elbow. Total scar excision was done on his left arm, forearm, elbow, and hand, and then followed by application of artificial dermis on to the wounds. After 2 weeks, neodermis formation was observed, after which an ultrathin split thickness skin graft was applied to the wounds. One month after sugery, the patient could extend his left elbow fully and the cosmetic result is satisfactory. Conclusion Use of artificial dermis should be a new alternative modality in improving our strategy in correcting scar issues from burn injuries, especially on large burn scar areas with limited donor sites for skin grafts.
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Chen, Yujie, Tengfei Ma, Xixi Yang, Jianmin Wang, Bosheng Song, and Xiangxiang Zeng. "MUFFIN: multi-scale feature fusion for drug–drug interaction prediction." Bioinformatics 37, no. 17 (March 15, 2021): 2651–58. http://dx.doi.org/10.1093/bioinformatics/btab169.
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Abstract Motivation Adverse drug–drug interactions (DDIs) are crucial for drug research and mainly cause morbidity and mortality. Thus, the identification of potential DDIs is essential for doctors, patients and the society. Existing traditional machine learning models rely heavily on handcraft features and lack generalization. Recently, the deep learning approaches that can automatically learn drug features from the molecular graph or drug-related network have improved the ability of computational models to predict unknown DDIs. However, previous works utilized large labeled data and merely considered the structure or sequence information of drugs without considering the relations or topological information between drug and other biomedical objects (e.g. gene, disease and pathway), or considered knowledge graph (KG) without considering the information from the drug molecular structure. Results Accordingly, to effectively explore the joint effect of drug molecular structure and semantic information of drugs in knowledge graph for DDI prediction, we propose a multi-scale feature fusion deep learning model named MUFFIN. MUFFIN can jointly learn the drug representation based on both the drug-self structure information and the KG with rich bio-medical information. In MUFFIN, we designed a bi-level cross strategy that includes cross- and scalar-level components to fuse multi-modal features well. MUFFIN can alleviate the restriction of limited labeled data on deep learning models by crossing the features learned from large-scale KG and drug molecular graph. We evaluated our approach on three datasets and three different tasks including binary-class, multi-class and multi-label DDI prediction tasks. The results showed that MUFFIN outperformed other state-of-the-art baselines. Availability and implementation The source code and data are available at https://github.com/xzenglab/MUFFIN.
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Martin, Pamela J., Paul Brown, Andrew V. Chapman, and Stuart Cook. "SILICA-REINFORCED EPOXIDIZED NATURAL RUBBER TIRE TREADS — PERFORMANCE AND DURABILITY." Rubber Chemistry and Technology 88, no. 3 (September 1, 2015): 390–411. http://dx.doi.org/10.5254/rct.15.85940.
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ABSTRACT Concerns regarding climate change and public health have compelled governments to reduce the environmental impact of transport. Many countries are introducing tire labeling and legislation targeting rolling resistance, wet grip, and noise. The proposed U.S. tire label also includes wear performance. Implementation of tire labeling is enabling buyers to choose better tires. The tire industry is responding to these demands and is developing the next generation of green tires. Current passenger tire tread technology is primarily petroleum based; however, the long-term availability of fossil-fuel supplies is limited. Thus a further step to minimize the environmental impact and carbon footprint of tires over their life cycle is to use sustainable materials not derived from fossil-fuels. Sumitomo Rubber Industries used epoxidized natural rubber (ENR) reinforced with silica in their route to a greener fossil-fuel free tire (the ENASAVE 100). At 25 mol% epoxidation, ENR has a glass transition temperature (Tg) most suitable for tread applications. Silica-filled ENR-25 tread compounds deliver lower rolling resistance, hence reduced fuel consumption, and enhanced wet and ice traction compared with benchmark premium passenger or truck treads. Optimization of wear performance to extend product durability is a current focus of research. However, correlation between laboratory abrasion and on-the-road tire wear is notoriously poor. The Tun Abdul Razak Research Centre (TARRC) have used light microscopy and transmission electron microscopy (TEM) to ascertain a mechanistic insight into tread wear, using results from wear studies on-the-road and laboratory abrasion. The results indicate that the mechanism of on-the-road tire wear differs from that of in-laboratory Akron abrasion tests.
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Xie, Yongjing, and Michael Butler. "Construction of an InstantPC-derivatized glycan glucose unit database: A foundation work for high-throughput and high-sensitivity glycomic analysis." Glycobiology 32, no. 4 (December 22, 2021): 289–303. http://dx.doi.org/10.1093/glycob/cwab128.
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Abstract The glycosylation profile of biotherapeutic glycoproteins is a critical quality attribute that is routinely monitored to ensure desired product quality, safety and efficacy. Additionally, as one of the most prominent and complex post-translational modifications, glycosylation plays a key role in disease manifestation. Changes in glycosylation may serve as a specific and sensitive biomarker for disease diagnostics and prognostics. However, the conventional 2-aminobenzamide-based N-glycosylation analysis procedure is time-consuming and insensitive with poor reproducibility. We have evaluated an innovative streamlined 96-well-plate-based platform utilizing InstantPC label for high-throughput, high-sensitivity glycan profiling, which is user-friendly, robust and ready for automation. However, the limited availability of InstantPC-labeled glycan standards has significantly hampered the applicability and transferability of this platform for expedited glycan structural profiling. To address this challenge, we have constructed a detailed InstantPC-labeled glycan glucose unit (GU) database through analysis of human serum and a variety of other glycoproteins from various sources. Following preliminary hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection separation and analysis, glycoproteins with complex glycan profiles were subjected to further fractionation by weak anion exchange HILIC and exoglycosidase sequential digestion for cross-validation of the glycan assignment. Hydrophilic interaction ultra-performance liquid chromatography coupled with electrospray ionization mass spectrometry was subsequently utilized for glycan fragmentation and accurate glycan mass confirmation. The constructed InstantPC glycan GU database is accurate and robust. It is believed that this database will enhance the application of the developed platform for high-throughput, high-sensitivity glycan profiling and that it will eventually advance glycan-based biopharmaceutical production and disease biomarker discovery.
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BLEIJERVELD, Onno B., Wil KLEIN, Arie B. VAANDRAGER, J. Bernd HELMS, and Martin HOUWELING. "Control of the CDPethanolamine pathway in mammalian cells: effect of CTP:phosphoethanolamine cytidylyltransferase overexpression and the amount of intracellular diacylglycerol." Biochemical Journal 379, no. 3 (May 1, 2004): 711–19. http://dx.doi.org/10.1042/bj20031422.
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For an insight regarding the control of PtdEtn (phosphatidylethanolamine) synthesis via the CDPethanolamine pathway, rat liver cDNA encoding ECT (CTP:phosphoethanolamine cytidylyltransferase) was transiently or stably transfected in Chinese-hamster ovary cells and a rat liver-derived cell line (McA-RH7777), resulting in a maximum of 26- and 4-fold increase in specific activity of ECT respectively. However, no effect of ECT overexpression on the rate of [3H]ethanolamine incorporation into PtdEtn was detected in both cell lines. This was explored further in cells overexpressing four times ECT activity (McA-ECT1). The rate of PtdEtn breakdown and PtdEtn mass were not changed in McA-ECT1 cells in comparison with control-transfected cells. Instead, an accumulation of CDPethanolamine (label and mass) was observed, suggesting that in McA-ECT1 cells the ethanolaminephosphotransferase-catalysed reaction became rate-limiting. However, overexpression of the human choline/ethanolaminephosphotransferase in McA-ECT1 and control-transfected cells had no effect on PtdEtn synthesis. To investigate whether the availability of DAG (diacylglycerol) limited PtdEtn synthesis in these cells, intracellular DAG levels were increased using PMA or phospholipase C. Exposure of cells to PMA or phospholipase C stimulated PtdEtn synthesis and this effect was much more pronounced in McA-ECT1 than in control-transfected cells. In line with this, the DAG produced after PMA exposure was consumed more rapidly in McA-ECT1 cells and the CDPethanolamine level decreased accordingly. In conclusion, our results suggest that the supply of CDPethanolamine, via the expression level of ECT, is an important factor governing the rate of PtdEtn biosynthesis in mammalian cells, under the condition that the amount of DAG is not limiting.
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Knyahnytska, Yuliya, Reza Zomorrodi, Tyler Kaster, Daphne Voineskos, Alisson Trevizol, and Daniel Blumberger. "The Safety, Clinical, and Neurophysiological Effects of Intranasal Ketamine in Patients Who Do Not Respond to Electroconvulsive Therapy: Protocol for a Pilot, Open-Label Clinical Trial." JMIR Research Protocols 11, no. 1 (January 17, 2022): e30163. http://dx.doi.org/10.2196/30163.
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Background Major depressive disorder is among the most disabling illnesses worldwide, with a lifetime prevalence of 16.2%. Research suggests that 20% to 40% of patients with depression do not respond to pharmacotherapy, developing treatment-resistant depression. Electroconvulsive therapy is the gold standard for treating individuals with treatment-resistant depression, with remission rates of approximately 75% to 90%. However, 10% to 25% of patients do not respond to electroconvulsive therapy, and many are unable to tolerate it due to the side effects. Both groups are considered to be patients who do not respond to electroconvulsive therapy, because both groups continue to exhibit symptoms of severe depression, have a limited number of treatment options available, and are in need of rapid treatment. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been shown to exert rapid antidepressant effects in patients with treatment-resistant depression when administered in subanesthetic doses through 40-minute intravenous infusions. Recently, a ketamine compound, esketamine (Spravato), that is administered through the intranasal route received regulatory approval by the US Food and Drug Administration and Health Canada to treat depression. However, esketamine is challenging to access due to high costs and limited availability. Racemic ketamine (rketamine) is cheap and easy to access; however, the effects in patients who have not responded to electroconvulsive therapy have yet to be understood or tested. This study will use transcranial magnetic stimulation to study mechanisms of human brain cortical physiology at the systemic level to identify neurobiomarkers of response. Objective The objective of this open-label pilot clinical trial is to test the feasibility and safety of intranasal ketamine in patients who have not responded to electroconvulsive therapy. The primary outcome is to determine the feasibility of a larger randomized controlled trial to test the efficacy of intranasal ketamine for patients who have not responded to electroconvulsive therapy for clinical indicators in unipolar depression. The secondary outcome is to determine the preliminary effects of an intervention on clinical outcomes, such as depressive symptoms, suicidal ideation, and quality of living. The third outcome is to explore neurophysiological changes as measured by transcranial magnetic stimulation electromyography and electroencephalography to measure changes in cortical excitability as potential predictors of clinical response. Methods A sterile solution of racemic ketamine hydrochloride will be administered twice per week for 4 weeks (8 sessions) intranasally to patients with treatment-resistant depression who did not respond to or could not tolerate an acute course of electroconvulsive therapy. We will recruit 25 adults (24-65 years old) over the course of 2 years from an academic psychiatric hospital in Toronto, Canada. Results This study has received ethics approval, and funding has been secured. The study is currently active. Conclusions This is the first study to test repeated doses of intranasal rketamine in patients who have not responded to electroconvulsive therapy for depression. Results from this study will (1) inform the development of a larger adequately powered randomized controlled trial to test the efficacy of intranasal ketamine for depression and (2) determine potential neurophysiological markers of clinical response. Trial Registration Clinical Trials.gov NCT05137938; http://clinicaltrials.gov/ct2/show/NCT05137938 International Registered Report Identifier (IRRID) PRR1-10.2196/30163
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Sharma, Pankaja, Soo Min Han, Nicola Gillies, Eric B. Thorstensen, Michael Goy, Matthew P. G. Barnett, Nicole C. Roy, David Cameron-Smith, and Amber M. Milan. "Circulatory and Urinary B-Vitamin Responses to Multivitamin Supplement Ingestion Differ between Older and Younger Adults." Nutrients 12, no. 11 (November 17, 2020): 3529. http://dx.doi.org/10.3390/nu12113529.
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Multivitamin and mineral (MVM) supplements are frequently used amongst older populations to improve adequacy of micronutrients, including B-vitamins, but evidence for improved health outcomes are limited and deficiencies remain prevalent. Although this may indicate poor efficacy of supplements, this could also suggest the possibility for altered B-vitamin bioavailability and metabolism in older people. This open-label, single-arm acute parallel study, conducted at the Liggins Institute Clinical Research Unit in Auckland, compared circulatory and urinary B-vitamer responses to MVM supplementation in older (70.1 ± 2.7 y, n = 10 male, n = 10 female) compared to younger (24.2 ± 2.8 y, n = 10 male, n = 10 female) participants for 4 h after the ingestion of a single dose of a commercial MVM supplement and standardized breakfast. Older adults had a lower area under the curve (AUC) of postprandial plasma pyridoxine (p = 0.02) and pyridoxal-5′phosphate (p = 0.03) forms of vitamin B6 but greater 4-pyridoxic acid AUC (p = 0.009). Urinary pyridoxine and pyridoxal excretion were higher in younger females than in older females (time × age × sex interaction, p < 0.05). Older adults had a greater AUC increase in plasma thiamine (p = 0.01), riboflavin (p = 0.009), and pantothenic acid (p = 0.027). In older adults, there was decreased plasma responsiveness of the ingested (pyridoxine) and active (pyridoxal-5′phosphate) forms of vitamin B6, which indicated a previously undescribed alteration in either absorption or subsequent metabolic interconversion. While these findings cannot determine whether acute B6 responsiveness is adequate, this difference may have potential implications for B6 function in older adults. Although this may imply higher B vitamin substrate requirements for older people, further work is required to understand the implications of postprandial differences in availability.
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Kaba, Mirgissa, Marlieke de Fouw, Kalkidan Solomon Deribe, Ephrem Abathun, Alexander Arnold Willem Peters, and Jogchum Jan Beltman. "Palliative care needs and preferences of female patients and their caregivers in Ethiopia: A rapid program evaluation in Addis Ababa and Sidama zone." PLOS ONE 16, no. 4 (April 22, 2021): e0248738. http://dx.doi.org/10.1371/journal.pone.0248738.
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Introduction In Ethiopia there is an extensive unmet need for palliative care, while the burden of non-communicable diseases and cancer is increasing. This study aimed to explore palliative care needs and preferences of patients, their caregivers, and the perspective of stakeholders on service provision in palliative programs for women, mostly affected by cervical cancer and breast cancer. Methods A rapid program evaluation using a qualitative study approach was conducted in three home-based palliative care programs in Addis Ababa and Yirgalem town, Ethiopia. Female patients enrolled in the programs, and their primary caregivers were interviewed on palliative care needs, preferences and service provision. We explored the views of purposely selected stakeholders on the organization of palliative care and its challenges. Audio-taped data was transcribed verbatim and translated into English and an inductive thematic analysis was applied. Descriptive analyses were used to label physical signs and symptoms using palliative outcome scale score. Results A total of 77 interviews (34 patients, 12 primary caregivers, 15 voluntary caregivers, 16 stakeholders) were conducted. The main physical complaints were moderate to severe pain (70.6%), followed by anorexia (50.0%), insomnia, nausea and vomiting (41.2%). Social interaction and daily activities were hampered by the patients’ condition. Both patients and caregivers reported that programs focus most on treatment of symptoms, with limited psychosocial, emotional, spiritual and economic support. Lack of organizational structures and policy directions limit the collaboration between stakeholders and the availability of holistic home-based palliative care services. Conclusions Although female patients and caregivers appreciated the palliative care and support provided, the existing services did not cover all needs. Pain management and all other needed supports were lacking. Multi-sectorial collaboration with active involvement of community-based structures is needed to improve quality of care and access to holistic palliative care services.
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González-Andrades, Miguel, Rosario Mata, María del Carmen González-Gallardo, Santiago Medialdea, Salvador Arias-Santiago, Juliana Martínez-Atienza, Antonio Ruiz-García, et al. "A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment." BMJ Open 7, no. 9 (September 2017): e016487. http://dx.doi.org/10.1136/bmjopen-2017-016487.
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IntroductionThere is a need to find alternatives to the use of human donor corneas in transplants because of the limited availability of donor organs, the incidence of graft complications, as well as the inability to successfully perform corneal transplant in patients presenting limbal deficiency, neo-vascularized or thin corneas, etc. We have designed a clinical trial to test a nanostructured fibrin-agarose corneal substitute combining allogeneic cells that mimics the anterior human native cornea in terms of optical, mechanical and biological behaviour.Methods and analysisThis is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in ten Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of this bioengineered human corneal substitute in adults with severe trophic corneal ulcers refractory to conventional treatment, or with sequelae of previous ulcers. In the initial phase of the trial (n=5), patients were sequentially recruited, with a safety period of 45 days, receiving the bioengineered corneal graft. In the second phase of the trial (currently ongoing), subjects are block randomised (2:1) to receive either the corneal graft (n=10), or amniotic membrane (n=5), as the control treatment. Adverse events, implant status, infection signs and induced neovascularization are evaluated as determinants of safety and feasibility of the bioengineered graft (main outcomes). Study endpoints are measured along a follow-up period of 24 months, including 27 post-implant assessment visits according to a decreasing frequency. Intention to treat, and per protocol, and safety analysis will be performed.Ethics and disseminationThe trial protocol received written approval by the corresponding Ethics Committee and the Spanish Regulatory Authority and is currently recruiting subjects. On completion of the trial, manuscripts with the results of phases I and II of the study will be published in a peer-reviewed journal.Trial registrationCT.gov identifier:NCT01765244(Jan2013). EudraCT number: 2010-024290-40 (Dec2012).
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Weiss, Jared, Brian D. Kavanagh, Allison Mary Deal, Timothy Zagar, Lawrence Bruce Marks, Tom Stinchcombe, Hossein Borghaei, et al. "Phase II study of stereotactic radiosurgery or other local ablation followed by erlotinib for patients with EGFR mutation who have previously progressed on an EGFR tyrosine kinase inhibitor (TKI)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20623-e20623. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20623.
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e20623 Background: For patients with metastatic EGFR mutated NSCLC, 1stline treatment with EGFR TKIs such as erlotinib result in a median PFS of about 10 months. In patients with a limited number of progressing lesions, local ablation therapy (LAT) of progressive lesions followed by re-initiation of TKI has shown promise in retrospective studies but to date this strategy has not been testing in prospective fashion. Methods: As part of an IRB approved open label prospective phase II trial (NCT01573702), patients with EGFR mutated NSCLC and immediate progression on a TKI in < 5 locations were treated with stereotactic radiosurgery (SRS) to progressing lesions followed by re-initiation of erlotinib. Our primary endpoint is PFS, and we hypothesize that it will be at least 3 months. Results: 25/40 planned patients have been enrolled and data is available on 23. By local reporting, 14 had exon 19, 5 had exon 21, 1 had compound exon 18 and exon 20, 1 had compound exon 19 and EML4/ALK and 2 were unknown. 65% were female, all were non-Hispanic white, median age 62.5 (range 43-85), PS0 65.2%/PS1 34.8%, median Charlson Comorbidity Index 6, and 71.4% were never smokers. Median number of lesions treated was 1 (range 1-3). Treated lesions included lung (14), bone (6), liver (3) and brain (2). There were no G3-4 AEs to SRS. Two subjects had grade 3 rash on erlotinib. Median PFS post treatment was 5.8 months (95% CI, 2.5 to 11.3) and median OS was 2.9 years (95% CI 1.1 to 2.9). Conclusions: LAT resulted in a modest extension in the duration of targeted therapy, supporting retrospective data in this population. Accrual to this study has been challenging due to the availability of 3rd generation EGFR TKIs and because LAT is often done outside of a clinical trial. Clinical trial information: NCT01573702.