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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
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 OSTI2019

Computed tomography (CT) in the evaluation of bladder and ureteral trauma: indications, technique, and diagnosis

Introduction: Trauma to the genitourinary system includes blunt and penetrating injuries to bladder and ureters. These are rare injuries and are overlooked as other abdominal and pelvic injuries often take priority. Delayed diagnosis can lead to significant morbidity and mortality. Computed tomography has taken a central role in the imaging of the ureters and bladder. Methods: This article reviews the anatomic relationships, mechanisms of injury, and clinical presentation to help physicians determine when bladder and ureteral injuries should be suspected and further imaging should be pursued. Radiologic evaluation of bladder and ureteral injury with CT cystography and CT urography, respectively, will be reviewed. Conclusion: CT cystography and CT urography are effective tools in identifying potentially serious injuries to the genitourinary system. Timely recognition of these injuries can be crucial for the overall management and prognosis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Clinical Outcomes of a Randomized Trial of Adaptive Plan-of-the-Day Treatment in Patients Receiving Ultra-hypofractionated Weekly Radiation Therapy for Bladder Cancer

Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

The Role of Adjuvant Chemoradiotherapy in Nonhilar Extrahepatic Bile Duct Cancer: A Long-Term Single-Institution Analysis

Despite frequent use in the clinical setting, especially for patients with high-risk factors for relapse, the role of adjuvant treatment has not been clarified in nonhilar extrahepatic bile duct cancer (NH-EHBDC). The goal of this study is to identify the role of adjuvant chemoradiotherapy (CRT) in NH-EHBDC patients after radical surgery.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Predictive Radiation Oncology – A New NCI–DOE Scientific Space and Community

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops—and a final concluding “World Café” on March 29, 2021—focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions—and collaborative parallel ideas—as the focus of work going forward to advance the field. These were then used to define short-term and longer-term “Blue Sky” goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2026

Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3–5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS. We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein–protein interaction networks-based algorithm PathFX. The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs. To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

Reimer, Richard J. [Stanford Univ., CA (United Sta↗
DOE OSTI2021

225 Ac/ 213 Bi Generator Based on Millifluidics Controlled Electrodeposition

Radioisotopes provide both diagnostic tools and therapeutic treatments for cancer and other diseases. In the US, millions of radioisotope doses are given to patients per year. Radiopharmaceutical generators are widely used to provide such short-lived medical radioisotopes in a clinical setting. These generators work by exploiting chemical differences in a parent/daughter isotope relationship. Actinium-225 (half-life 10 d) is used to provide clinically useful amounts of daughter isotopes 213 Bi (46 m). An integrated millifluidic 225 Ac/ 213 Bi radiopharmaceutical generator device was engineered to produce 213 Bi labeled biomolecules. Using recent LANL successes in additive manufacturing of small-scale fluidic devices, a disposable device was developed that integrates three steps for the production of 213 Bi labeled antibodies: 1) 213 Bi separation from 225 Ac parent, 2) 213 Bi antibody labeling, and 3) purification of the labelled antibody.

213Bi↗
DOE OSTI2021

Combining Clinical and Dosimetric Features in a PBS Proton Therapy Cohort to Develop a NTCP Model for Radiation-Induced Optic Neuropathy

Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Overcoming Barriers to Radiopharmaceutical Therapy (RPT): An Overview From the NRG-NCI Working Group on Dosimetry of Radiopharmaceutical Therapy

Radiopharmaceutical therapy (RPT) continues to demonstrate tremendous potential in improving the therapeutic gains in radiation therapy by specifically delivering radiation to tumors that can be well assessed in terms of dosimetry and imaging. Dosimetry in external beam radiation therapy is standard practice. This is not the case, however, in RPT. This NRG (acronym formed from the first letter of the 3 original groups: National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group)-National Cancer Institute Working Group review describes some of the challenges to improving RPT. The main priorities for advancing the field include (1) developing and adopting best practice guidelines for incorporating patient-specific dosimetry for RPT that can be used at both large clinics with substantial resources and more modest clinics that have limited resources, (2) establishing and improving strategies for introducing new radiopharmaceuticals for clinical investigation, (3) developing approaches to address the radiophobia that is associated with the administration of radioactivity for cancer therapy, and (4) solving the financial and logistical issues of expertise and training in the developing field of RPT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Singleplex, multiplex and pooled sample real-time RT-PCR assays for detection of SARS-CoV-2 in an occupational medicine setting

Abstract For workplaces which cannot operate as telework or remotely, there is a critical need for routine occupational SARS-CoV-2 diagnostic testing. Although diagnostic tests including the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel (CDC Diagnostic Panel) (EUA200001) were made available early in the pandemic, resource scarcity and high demand for reagents and equipment necessitated priority of symptomatic patients. There is a clearly defined need for flexible testing methodologies and strategies with rapid turnaround of results for (1) symptomatic, (2) asymptomatic with high-risk exposures and (3) asymptomatic populations without preexisting conditions for routine screening to address the needs of an on-site work force. We developed a distinct SARS-CoV-2 diagnostic assay based on the original CDC Diagnostic Panel (EUA200001), yet, with minimum overlap for currently employed reagents to eliminate direct competition for limited resources. As the pandemic progressed with testing loads increasing, we modified the assay to include 5-sample pooling and amplicon target multiplexing. Analytical sensitivity of the pooled and multiplexed assays was rigorously tested with contrived positive samples in realistic patient backgrounds. Assay performance was determined with clinical samples previously assessed with an FDA authorized assay. Throughout the pandemic we successfully tested symptomatic, known contact and travelers within our occupational population with a ~ 24–48-h turnaround time to limit the spread of COVID-19 in the workplace. Our singleplex assay had a detection limit of 31.25 copies per reaction. The three-color multiplexed assay maintained similar sensitivity to the singleplex assay, while tripling the throughput. The pooling assay further increased the throughput to five-fold the singleplex assay, albeit with a subtle loss of sensitivity. We subsequently developed a hybrid ‘multiplex-pooled’ strategy to testing to address the need for both rapid analysis of samples from personnel at high risk of COVID infection and routine screening. Herein, our SARS-CoV-2 assays specifically address the needs of occupational healthcare for both rapid analysis of personnel at high-risk of infection and routine screening that is essential for controlling COVID-19 disease transmission. In addition to SARS-CoV-2 and COVID-19, this work demonstrates successful flexible assays developments and deployments with implications for emerging highly transmissible diseases and future pandemics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The Clinical Cell-Cycle Risk (CCR) score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation

The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Efficacy of an inactivated Senecavirus A vaccine in weaned pigs and mature sows

Senecavirus A (SVA), commonly known as Seneca Valley virus (SVV) is a causative agent for vesicular disease in swine. It has been found across the globe including the United States, Brazil, and China. Clinical disease caused by this virus is identical to foot-and-mouth disease virus (FMDV). Since FMDV has the potential to cause severe economic consequences in FMDV-free countries, those countries are on high alert for signs of vesicles in swine and an investigation is performed to rule out the presence of FMDV if observed. In countries where SVA cases have continued to occur, investigations and testing can cause a burden on personnel and resources. The objectives of this study were to test the efficacy of a whole-virus inactivated SVA vaccine against challenge in nursery-aged pigs, mature sows, and to assess the protection of passive maternal immunity generated by immunized dams. Animals were given two doses of the vaccine intramuscularly three weeks apart and challenged intranasally two weeks after the second dose. Non-vaccinated animals challenged with SVA developed clinical signs of disease, replicated virus, and developed a neutralizing antibody response. Vaccinated animals had robust neutralizing titers after two doses; and after challenge, did not develop vesicular disease and had limited rectal shedding. Piglets suckling immunized dams and challenged with SVA at 3–6 days-of-age had neutralizing titers prior to challenge and did not replicate or shed virus. An efficacious vaccine could improve swine welfare and reduce the economic consequences of continued foreign animal disease investigations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity

Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer–Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Interactions of Cells and Biomaterials for Nerve Tissue Engineering: Polymers and Fabrication

Neural injuries affect millions globally, significantly impacting their quality of life. The inability of these injuries to heal, limited ability to regenerate, and the lack of available treatments make regenerative medicine and tissue engineering a promising field of research for developing methods for nerve repair. This review evaluates the use of natural and synthetic polymers, and the fabrication methods applied that influence a cell’s behavior. Methods include cross-linking hydrogels, incorporation of nanoparticles, and 3D printing with and without live cells. The endogenous cells within the injured area and any exogenous cells seeded on the polymer construct play a vital role in regulating healthy neural activity. This review evaluates the body’s local and systemic reactions to the implanted materials. Although numerous variables are involved, many of these materials and methods have exhibited the potential to provide a biomaterial environment that promotes biocompatibility and the regeneration of a physical and functional nerve. Future studies may evaluate advanced methods for modifying material properties and characterizing the tissue–biomaterial interface for clinical applications.

3D printing↗
DOE OSTI2023

Restrictive spirometry pattern among construction trade workers

Spirometry-based studies of occupational lung disease have mostly focused on obstructive or mixed obstructive/restrictive outcomes. We wanted to determine if restrictive spirometry pattern (RSP) is associated with occupation and increased mortality. Study participants included 18,145 workers with demographic and smoking data and repeatable spirometry. The mortality analysis cohort included 15,445 workers with known vital status and cause of death through December 31, 2016. Stratified analyses explored RSP prevalence by demographic and clinical variables and trade. Log-binomial regression models explored RSP risk factors while controlling for important confounders such as smoking, obesity, and comorbidities. Cox regression models explored mortality risk by spirometry category. Prevalence of RSP was very high (28.6%). Mortality hazard ratios for RSP were 1.50 for all causes, 1.86 for cardiovascular diseases, 2.31 for respiratory diseases, and 1.66 for lung cancer. All construction trades except painters, machinists, and roofers had significantly elevated risk for RSP compared to our internal reference group. RSP was significantly associated with both parenchymal and pleural changes seen by chest X-ray. Construction trade workers are at significantly increased risk for RSP independent of obesity. Individuals with RSP are at increased risk for all-cause mortality as well as mortality attributable to respiratory diseases, cardiovascular diseases, and lung cancer. RSP deserves greater attention in occupational medicine and epidemiology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Subject-specific multi-scale modeling of the fate of inhaled aerosols

Determining the fate of inhaled aerosols in the respiratory system is essential in assessing the potential toxicity of inhaled airborne materials, responses to airborne pathogens, or in improving inhaled drug delivery. The availability of high-resolution clinical lung imaging and advances in the reconstruction of lung airways from CT images have led to the development of subject-specific in-silico 3D models of aerosol dosimetry, often referred to as computational fluid-particle-dynamics (CFPD) models. As CFPD models require extensive computing resources, they are typically confined to the upper and large airways. These models can be combined with lower-dimensional models to form multiscale models that predict the transport and deposition of inhaled aerosols in the entire respiratory tract. Understanding where aerosols deposit is only the first of potentially several key events necessary to predict an outcome, being a detrimental health effect or a therapeutic response. To that end, multiscale approaches that combine CFPD with physiologically-based pharmacokinetics (PBPK) models have been developed to evaluate the absorption, distribution, metabolism, and excretion (ADME) of toxic or medicinal chemicals in one or more compartments of the human body. CFPD models can also be combined with host cell dynamics (HCD) models to assess regional immune system responses. Here, this paper reviews the state of the art of these different multiscale approaches and discusses the potential role of personalized or subject-specific modeling in respiratory health.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

CASTELO: clustered atom subtypes aided lead optimization—a combined machine learning and molecular modeling method

Background: Drug discovery is a multi-stage process that comprises two costly major steps: pre-clinical research and clinical trials. Among its stages, lead optimization easily consumes more than half of the pre-clinical budget. We propose a combined machine learning and molecular modeling approach that partially automates lead optimization workflow in silico, providing suggestions for modification hot spots. Results: The initial data collection is achieved with physics-based molecular dynamics simulation. Contact matrices are calculated as the preliminary features extracted from the simulations. To take advantage of the temporal information from the simulations, we enhanced contact matrices data with temporal dynamism representation, which are then modeled with unsupervised convolutional variational autoencoder (CVAE). Finally, conventional and CVAE-based clustering methods are compared with metrics to rank the submolecular structures and propose potential candidates for lead optimization. Conclusion: With no need for extensive structure-activity data, our method provides new hints for drug modification hotspots which can be used to improve drug potency and reduce the lead optimization time. It can potentially become a valuable tool for medicinal chemists.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Modern Radiation Therapy for Extranodal Nasal-Type NK/T-cell Lymphoma: Risk-Adapted Therapy, Target Volume, and Dose Guidelines from the International Lymphoma Radiation Oncology Group

In the multidisciplinary management of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL), with curative intent, radiation therapy is the most efficacious modality and is an essential component of a combined-modality regimen. In the past decade, utilization of upfront radiation therapy and non–anthracycline-based chemotherapy has improved treatment and prognosis. This guideline mainly addresses the heterogeneity of clinical features, principles of risk-adapted therapy, and the role and appropriate design of radiation therapy. Radiation therapy methods (including target volume definition, dose and delivery methods) are crucial for optimizing cure for patients with early-stage ENKTCL. The application of the principles of involved site radiation therapy in this lymphoma entity often leads to a more extended clinical target volume (CTV) than in other lymphoma types because it usually presents with primary tumor invasion, multifocal lesions, or extensive submucosal infiltration beyond the macroscopic disease. The CTV varies across different primary sites and is classified mainly into nasal, nonnasal upper aerodigestive tract (UADT), and extra-UADT entities. This review is a consensus of the International Lymphoma Radiation Oncology Group regarding the approach to radiation therapy, target-volume definition, optimal dose, and dose constraints in ENKTCL treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗