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All sources NASA NTRS DOE OSTI

DOE OSTI2015

Using Clinical Data, Hypothesis Generation Tools and PubMed Trends to Discover the Association between Diabetic Retinopathy and Antihypertensive Drugs

Diabetic retinopathy (DR) is a leading cause of blindness and common complication of diabetes. Many diabetic patients take antihypertensive drugs to prevent cardiovascular problems, but these drugs may have unintended consequences on eyesight. Six common classes of antihypertensive drug are angiotensin converting enzyme (ACE) inhibitors, alpha blockers, angiotensin receptor blockers (ARBs), -blockers, calcium channel blockers, and diuretics. Analysis of medical history data might indicate which of these drugs provide safe blood pressure control, and a literature review is often used to guide such analyses. Beyond manual reading of relevant publications, we sought to identify quantitative trends in literature from the biomedical database PubMed to compare with quantitative trends in the clinical data. By recording and analyzing PubMed search results, we found wide variation in the prevalence of each antihypertensive drug in DR literature. Drug classes developed more recently such as ACE inhibitors and ARBs were most prevalent. We also identified instances of change-over-time in publication patterns. We then compared these literature trends to a dataset of 500 diabetic patients from the UT Hamilton Eye Institute. Data for each patient included class of antihypertensive drug, presence and severity of DR. Graphical comparison revealed that older drug classes such as diuretics, calcium channel blockers, and -blockers were much more prevalent in the clinical data than in the DR and antihypertensive literature. Finally, quantitative analysis of the dataset revealed that patients taking -blockers were statistically more likely to have DR than patients taking other medications, controlling for presence of hypertension and year of diabetes onset. This finding was concerning given the prevalence of -blockers in the clinical data. We determined that clinical use of -blockers should be minimized in diabetic patients to prevent retinal damage.

Big data↗

DOE OSTI2021

Supervised learning with word embeddings derived from PubMed captures latent knowledge about protein kinases and cancer

Abstract Inhibiting protein kinases (PKs) that cause cancers has been an important topic in cancer therapy for years. So far, almost 8% of >530 PKs have been targeted by FDA-approved medications, and around 150 protein kinase inhibitors (PKIs) have been tested in clinical trials. We present an approach based on natural language processing and machine learning to investigate the relations between PKs and cancers, predicting PKs whose inhibition would be efficacious to treat a certain cancer. Our approach represents PKs and cancers as semantically meaningful 100-dimensional vectors based on word and concept neighborhoods in PubMed abstracts. We use information about phase I-IV trials in ClinicalTrials.gov to construct a training set for random forest classification. Our results with historical data show that associations between PKs and specific cancers can be predicted years in advance with good accuracy. Our tool can be used to predict the relevance of inhibiting PKs for specific cancers and to support the design of well-focused clinical trials to discover novel PKIs for cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Mining locus tags in PubMed Central to improve microbial gene annotation

Background: The scientific literature contains millions of microbial gene identifiers within the full text and tables, but these annotations rarely get incorporated into public sequence databases. We propose to utilize the Open Access (OA) subset of PubMed Central (PMC) as a gene annotation database and have developed an R package called pmcXML to automatically mine and extract locus tags from full text, tables and supplements. Results: We mined locus tags from 1835 OA publications in ten microbial genomes and extracted tags mentioned in 30,891 sentences in main text and 20,489 rows in tables. We identified locus tag pairs marking the start and end of a region such as an operon or genomic island and expanded these ranges to add another 13,043 tags. We also searched for locus tags in supplementary tables and publications outside the OA subset in Burkholderia pseudomallei K96243 for comparison. There were 168 publications containing 48,470 locus tags and 83% of mentions were from supplementary materials and 9% from publications outside the OA subset. Conclusions: B. pseudomallei locus tags within the full text and tables of OA publications represent only a small fraction of the total mentions in the literature. For microbial genomes with very few functionally characterized proteins, the locus tags mentioned in supplementary tables and within ranges like genomic islands contain the majority of locus tags. Significantly, the functions in the R package provide access to additional resources in the OA subset that are not currently indexed or returned by searching PMC.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Fate of Manuscripts Rejected From the Red Journal

Purpose: To evaluate characteristics associated with higher rates of acceptance for original manuscripts submitted for publication to the International Journal of Radiation Oncology • Biology • Physics (IJROBP) and describe the fate of rejected manuscripts. Methods and Materials: Manuscripts submitted to the IJROBP from May 1, 2010, to August 31, 2010, and May 1, 2012, to August 31, 2012, were evaluated for author demographics and acceptance status. A PubMed search was performed for each IJROBP-rejected manuscript to ascertain whether the manuscript was ultimately published elsewhere. The Impact Factor of the accepting journal and the number of citations of the published manuscript were also collected. Results: Of the 500 included manuscripts, 172 (34.4%) were accepted and 328 (65.6%) were rejected. There was no significant difference in acceptance rates according to gender or degree of the submitting author, but there were significant differences seen based on the submitting author's country, rank, and h-index. On multivariate analysis, earlier year submitted (P<.0001) and higher author h-index (P=.006) remained significantly associated with acceptance into the IJROBP. Two hundred thirty-five IJROBP-rejected manuscripts (71.7%) were ultimately published in a PubMed-listed journal as of July 2014. There were no significant differences in any submitting author characteristics. Journals accepting IJROBP-rejected manuscripts had a lower median [interquartile range] 2013 impact factor compared with the IJROBP (2.45 [1.53-3.71] vs 4.176). The IJROBP-rejected manuscripts ultimately published elsewhere had a lower median [interquartile range] number of citations (1 [0-4] vs 6 [2-11]; P<.001), which persisted on multivariate analysis. Conclusions: The acceptance rate for manuscripts submitted to the IJROBP is approximately one-third, and approximately 70% of rejected manuscripts are ultimately published in other PubMed-listed journals, but these ultimate-destination journals usually have a lower impact factor, leading to fewer citations and overall visibility.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Erratum to: Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer

In the version of this article that was published on PubMed [1] the author’s name “Mark A. Dane” was formatted incorrectly in the XML mark up and therefore appeared incorrectly on PubMed. In the XML mark up, the middle initial “A” was added as a Particle when it should have been included as a Given Name. Due to this error, the author’s name was incorrectly formatted in PubMed as “A Dane M” and not as “Dane MA”. The author’s name is correct on the BioMed Central website. The author's name in the XML of the original article [1] has been updated accordingly.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2017

Endovascular Therapy Research in Lower Limb Peripheral Arterial Disease Published Over a 5-Year Period: Who is Publishing and Where?

IntroductionPeripheral arterial disease (PAD) is being increasingly managed by endovascular therapies. In this study, we identified the clinical services publishing research as well as the journals of publication over a 5-year period.MethodsTwenty keywords and phrases related to endovascular intervention were identified, and a literature search was performed through the PubMed database from January 2009 to January 2014. Inclusion criteria were English language, study population more than five patients, and matching the keyword search. Eligible studies were collated into a database and classified by journal of publication, PubMed number, article title, publishing clinical service, type of publication, country of origin, and authors.Results825 studies from 114 different journals were identified. 297 papers were excluded. Of the 528 included papers, 204 (39%) were published by Vascular Surgery (VS), 157 (30%) by Interventional Radiology (IR), 101 (19%) by Cardiology, 43 (8%) by Angiology, 6 (1%) by Vascular Medicine, and 17 (3%) from miscellaneous services. 283 (54%) studies originated from Europe, 157 (30%) from North America, 76 (14%) from Asia, 6 from Australia, 3 each from South America and Africa. IR published the most papers on PAD endovascular intervention in Europe with VS second while this trend was reversed in the USA. The 528 papers were published in 98 different journals with retrospective case series (72%), the majority.ConclusionIR continues to play a significant research role in endovascular intervention in PAD, particularly in Europe, and specifically in below the knee intervention, pedal intervention, and drug-eluting technologies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Radiation Oncology Resident Research Productivity in the United States: 2015 to 2019

Multiple efforts have been made in recent years to establish national benchmarks for research productivity among US radiation oncology residents. Morgan et al found a mean of 1.01 first-author, PubMed-searchable articles published by US radiation oncology residents over 4 years of residency between 2002 and 2007, whereas Verma et al found a mean of 1.97 first-author, PubMed-searchable articles published by members of the graduating US radiation oncology residency classes of 2014 and 2015. In this study, we sought to establish new national benchmarks for US radiation oncology resident research productivity and characterize the scholarly work produced by graduating US radiation oncology residents.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Advancements and Application of Microsecond Synchrotron X-ray Footprinting at the Advanced Light Source

The method of synchrotron X-ray protein footprinting (XF-MS) is used to determine protein conformational changes, folding, protein-protein and protein-ligand interactions, providing information which is often difficult to obtain using X-ray crystallography and other common structural biology methods [1–3]. The technique uses comparative in situ labeling of solvent-accessible side chains by highly reactive hydroxyl radicals (•OH) in buffered aqueous solution under different assay conditions. In regions where a protein is folded or binds a partner, these •OH susceptible sites are inaccessible to solvent, and therefore protected from labeling. The •OH are generated by the ionization of water using high-flux-density X-rays. High-flux density is a key factor for XF-MS labeling because obtaining an adequate steady-state concentration of hydroxyl radical within a short irradiation time is necessary to minimize radiation-induced secondary damage and also to overcome various scavenging reactions that reduce the yield of labeled side chains.

47 OTHER INSTRUMENTATION↗

DOE OSTI2016

Muscle Logic: New Knowledge Resource for Anatomy Enables Comprehensive Searches of the Literature on the Feeding Muscles of Mammals

Here we present the Mammalian Feeding Muscle Ontology (MFMO), a multi-species ontology focused on anatomical structures that participate in feeding and other oral/pharyngeal behaviors. A unique feature of the MFMO is that a simple, computable, definition of each muscle, which includes its attachments and innervation, is true across mammals. This construction mirrors the logical foundation of comparative anatomy and permits searches using language familiar to biologists. Further, it provides a template for muscles that will be useful in extending any anatomy ontology. The MFMO is developed to support the Feeding Experiments End-User Database Project (FEED, https://feedexp.org/), a publicly-available, online repository for physiological data collected from in vivo studies of feeding (e.g., mastication, biting, swallowing) in mammals. Currently the MFMO is integrated into FEED and also into two literature-specific implementations of Textpresso, a text-mining system that facilitates powerful searches of a corpus of scientific publications. We evaluate the MFMO by asking questions that test the ability of the ontology to return appropriate answers (competency questions). Lastly, we compare the results of queries of the MFMO to results from similar searches in PubMed and Google Scholar. Our tests demonstrate that the MFMO is competent to answer queries formed in the common language of comparative anatomy, but PubMed and Google Scholar are not. Overall, our results show that by incorporating anatomical ontologies into searches, an expanded and anatomically comprehensive set of results can be obtained. The broader scientific and publishing communities should consider taking up the challenge of semantically enabled search capabilities.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2017

Ocular Pathogens, Eye Infections, and Cosmetics Periodic Update (July 1, 2016 to June 30, 2017)

A PubMed literature search was conducted to support analyses and investigations of the relationship between microorganisms associated with human eye infections (including opportunistic pathogens) and cosmetics. Key terms for PubMed literature searches included; microbial genera and species of interest (bacteria, viruses, fungi, protozoans, parasites), opportunistic pathogens, human eye disease and infection, human ocular infections, specific eye diseases (keratitis, conjunctivitis, etc.), eye accidents, eye surgery, contacts, infants, pregnant women, geriatric, immunocompromised, HIV and polymicrobial. The number of journal articles for defined searches was summarized and journal citations and abstracts were cataloged and incorporated into a searchable information system (MS Access). A periodic update to the literature searches was conducted in July 2017 and observations from the update indicate the most commonly associated bacteria with eye infections/diseases were Staphylococcus sp., Chlamydia sp. and Pseudomonas sp. Also, the literature searches indicate the most commonly associated fungi with eye infections/diseases were Fusarium sp., Aspergillus sp. and Candida sp. A relative rank of occurrence of microorganisms associated with eye infections/disease in the literature citations was; Staphylococcus aureus, Chlamydia trachomatis, Cytomegalovirus, Herpes zoster virus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Acanthamoeba sp., Fusarium sp., E. coli and Mycobacterium tuberculosis. Literature searches for opportunistic microorganisms and emerging pathogens for this update identified several articles on fungi, Bacillus sp. (primarily B. cereus), Haemophilus influenzae and Human Papillomavirus (HPV) associated with eye infections/diseases. Although the literature searches focused on microorganisms, key eye diseases noted in the citations were keratitis, conjunctivitis, corneal ulcers, endophthalmitis and keratoconjunctivitis.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2012

Open Peer Review by a Selected-Papers Network

A selected-papers (SP) network is a network in which researchers who read, write, and review articles subscribe to each other based on common interests. Instead of reviewing a manuscript in secret for the Editor of a journal, each reviewer simply publishes his review (typically of a paper he wishes to recommend) to his SP network subscribers. Once the SP network reviewers complete their review decisions, the authors can invite any journal editor they want to consider these reviews and initial audience size, and make a publication decision. Since all impact assessment, reviews, and revisions are complete, this decision process should be short. I show how the SP network can provide a new way of measuring impact, catalyze the emergence of new subfields, and accelerate discovery in existing fields, by providing each reader a fine-grained filter for high-impact. I present a three phase plan for building a basic SP network, and making it an effective peer review platform that can be used by journals, conferences, users of repositories such as arXiv, and users of search engines such as PubMed. I show how the SP network can greatly improve review and dissemination of research articles in areas that are not well-supported by existing journals. Finally, I illustrate how the SP network concept can work well with existing publication services such as journals, conferences, arXiv, PubMed, and online citation management sites.

60 APPLIED LIFE SCIENCES↗

NASA NTRSDate not supplied

Introduction of the NASA Microgravity Research Library

As opportunities for conducting experiments in space are rare, more studies have been published using ground-based analogs that simulate microgravity conditions. For example, when conducting a literature search in PubMed for peer-reviewed articles and studies that used simulated microgravity conditions, results will yield over 5,000 publications dating back to 1961. The issue with this search technique and medium is that these articles are vast in quantity and spread out across multiple web-based databases, repositories, and libraries; some of which, are wholly inaccessible. For example, in PubMed for a single year, we found 1,000+ microgravity research articles among more than 12,000 general, space research articles; these, were within an overarching 350,000+ total, general medical research articles for just 2020. The KSC Microgravity Simulation Support Facility (MSSF), with support from the KSC Information Technology (IT) Applications Development Team and the NASA Space Biology Program, took the initiative to develop a database that would serve as the central repository for existing microgravity research. This repository site is open to the public and houses not only peer-reviewed publications relating to microgravity research, but also dissertations, technical publications such as white papers, NASA technical publications, and patent publications. In this presentation, we will discuss some of our literature research findings as well as present a working prototype version of the Library. It is our goal that the future infrastructure of this database advance to become a fully-functional, NASA Space Life-Sciences Research Library.

Anna Maria Ruby↗

NASA NTRSDate not supplied

Introduction of the NASA Microgravity Research Library

Anna Maria Ruby↗

DOE OSTI2025

The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease

Importance The success of recent randomized clinical trials (RCTs) for Alzheimer disease (AD), particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored. Objective To describe temporal changes in the features of RCT design for interventions in AD. Evidence Review PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included. Four assessors independently reviewed full-text articles to capture study characteristics. Main Outcomes and Measures The number of participants and the duration of RCTs as well as the target population, outcomes, and funding were extracted from published reports. These features were analyzed with respect to time using linear regression and χ 2 analyses. Results The study included 203 RCTs with 79 589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]). RCT transparency improved, with more frequent data accessibility statements, registered reports, and better reporting on race and ethnicity. Conclusions and Relevance This methodology research of AD RCTs highlights substantial changes in key features of AD clinical trials from 1992 to 2024. AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.

General & Internal Medicine↗

DOE OSTI2022

Association of clonal hematopoiesis mutations with clinical outcomes: A systematic review and meta-analysis

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26–2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31–9.45, p < .0001), therapy-related myeloid neoplasms (four studies; HR = 7.55, 95% CI = 4.3–13.57, p < .001), and death (nine studies; HR = 1.34, 95% CI = 1.2–1.5, p < .0001). The cardiovascular disease analysis was further stratified by variant allele fraction (VAF) and gene, which showed a statistically significant association only with a VAF of ≥ 10% (HR = 1.42, 95% CI = 1.24–1.62, p < .0001), as well as statistically significant associations for each gene examined with the largest magnitude of effect found for CH mutations in JAK2 (HR = 3.5, 95% CI = 1.84–6.68, p < .0001). Analysis of the association of CH mutations with hematologic malignancy demonstrated a numeric stepwise increase in risk with increasing VAF thresholds. This analysis strongly supports the association of CH mutations with a clinically meaningful increased risk of adverse clinical outcomes among individuals without hematologic disease, particularly with increasing VAF thresholds.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

A review of stereotactic body radiotherapy – is volumetric modulated arc therapy the answer?

Stereotactic body radiotherapy (SBRT) is a high precision radiotherapy technique used for the treatment of small to moderate extra-cranial tumours. Early studies utilising SBRT have shown favourable outcomes. However, major disadvantages of static field SBRT include long treatment times and toxicity complications. Volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) may potentially mitigate these disadvantages. This review aims to assess the feasibility of emerging VMAT and IMRT-based SBRT treatment techniques and qualify which offers the best outcome for patients, whilst identifying any emerging and advantageous SBRT planning trends. A review and synthesis of data from current literature up to September 2013 was conducted on EMBASE, Medline, PubMed, Science Direct, Proquest central, Google Scholar and the Cochrane Database of Systematic reviews. Only full text papers comparing VMAT and or IMRT and or Static SBRT were included. Ten papers were identified that evaluated the results of VMAT/IMRT SBRT. Five related to medically inoperable stage 1 and 2 non-small-cell lung cancer (NSCLC), three to spinal metastasis, one related to abdominal lymph node malignancies, with the final one looking at pancreatic adenocarcinoma. Overall treatment times with VMAT were reduced by 66–70% for lung, 46–58% for spine, 42% and 21% for lymph node and pancreatic metastasis respectively, planning constraints were met with several studies showing improved organs at risk sparing with IMRT/VMAT to static SBRT. Both IMRT and VMAT were able to meet all planning constraints in the studies reviewed, with VMAT offering the greatest treatment efficiency. Early clinical outcomes with VMAT and IMRT SBRT have demonstrated excellent local control and favourable survival outcomes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

The cardiac dose-sparing benefits of deep inspiration breath-hold in left breast irradiation: a systematic review

Despite technical advancements in breast radiation therapy, cardiac structures are still subject to significant levels of irradiation. As the use of adjuvant radiation therapy after breast-conserving surgery continues to improve survival for early breast cancer patients, the associated radiation-induced cardiac toxicities become increasingly relevant. Our primary aim was to evaluate the cardiac-sparing benefits of the deep inspiration breath-hold (DIBH) technique. An electronic literature search of the PubMed database from 1966 to July 2014 was used to identify articles published in English relating to the dosimetric benefits of DIBH. Studies comparing the mean heart dose of DIBH and free breathing treatment plans for left breast cancer patients were eligible to be included in the review. Studies evaluating the reproducibility and stability of the DIBH technique were also reviewed. Ten studies provided data on the benefits of DIBH during left breast irradiation. From these studies, DIBH reduced the mean heart dose by up to 3.4 Gy when compared to a free breathing approach. Four studies reported that the DIBH technique was stable and reproducible on a daily basis. According to current estimates of the excess cardiac toxicity associated with radiation therapy, a 3.4 Gy reduction in mean heart dose is equivalent to a 13.6% reduction in the projected increase in risk of heart disease. DIBH is a reproducible and stable technique for left breast irradiation showing significant promise in reducing the late cardiac toxicities associated with radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2020

Aggregation and analysis of indication-symptom relationships for drugs approved in the USA

Abstract Purpose Drug indications and disease symptoms often confound adverse event reports in real-world datasets, including electronic health records and reports in the FDA Adverse Event Reporting System (FAERS). A thorough, standardized set of indications and symptoms is needed to identify these confounders in such datasets for drug research and safety assessment. The aim of this study is to create a comprehensive list of drug-indication associations and disease-symptom associations using multiple resources, including existing databases and natural language processing. Methods Drug indications for drugs approved in the USA were extracted from two databases, RxNorm and Side Effect Resource (SIDER). Symptoms for these indications were extracted from MedlinePlus and using natural language processing from PubMed abstracts. Results A total of 1361 unique drugs, 1656 unique indications, and 2201 unique symptoms were extracted from a wide variety of MedDRA System Organ Classes. Text-mining precision was maximized at 0.65 by examining Term Frequency Inverse Document Frequency (TF-IDF) scores of the disease-symptom associations. Conclusion The drug-indication associations and disease-symptom associations collected in this study may be useful in identifying confounders in other datasets, such as safety reports. With further refinement and additional drugs, indications, and symptoms, this dataset may become a quality resource for disease symptoms.

Punyala, Ananth↗