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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials

Abstract Background Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience. Methods Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug. Results In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR. Conclusions DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.

Immunology↗
DOE OSTI2019

Upper urinary tract urothelial carcinoma on multidetector CT: spectrum of disease

Urothelial carcinoma of the upper urinary tract (UUT) is a relatively uncommon genitourinary malignancy, accounting for about 5–7% of urothelial tumors. The significant features of this tumor are multifocality and high rate of recurrence. Computed tomography urography (CTU) has replaced excretory urography (EU) and retrograde pyelography (RP) for imaging of upper tract urothelial carcinoma. While many studies have confirmed high sensitivity (88–100%) and specificity (93–100%) of CTU, an optimized CT protocol is of critical importance in screening, staging, and post-operative follow-up of patients (Chlapoutakis, Eur J Radiol 73(2):334–338, 2010; Caoli and Cohan, Abdom Radiol (NY) 41(6):1100–1107, 2016). The key element of the CT protocol is to have adequate distension of the collecting system with excreted contrast, to detect subtle lesions at an early stage. In this article, we discuss the background of upper urinary tract TTC, pathogenesis, CT protocol and the role of imaging in evaluation of this malignancy, staging, as well as different imaging appearances.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Discordant Clinical and Microbiological Outcomes Are Associated With Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections

Abstract Background Current US Food and Drug Administration guidance recommends that the primary endpoint for complicated urinary tract infection clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed point after therapy. Although some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as treatment failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. Methods We analyzed participant data from 13 phase 3 clinical trials submitted to the US Food and Drug Administration (N = 4842). Outcomes were determined at the test of cure (TOC) visit, recommended to occur at least 5 days after therapy and at the late follow-up visit, recommended to occur 21 to 28 days after randomization. Clinical and microbiological success were defined as the resolution of complicated urinary tract infection symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication). Results Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the late follow-up visit, and the risk of late clinical failure increased with time. Conclusions Discordant clinical and microbiological outcomes at the TOC visit were associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component of the endpoint.

Immunology↗
DOE OSTI2021

Using Lactobacilli to Fight Escherichia coli and Staphylococcus aureus Biofilms on Urinary Tract Devices

The low efficacy of conventional treatments and the interest in finding natural-based approaches to counteract biofilm development on urinary tract devices have promoted the research on probiotics. This work evaluated the ability of two probiotic strains, Lactobacillus plantarum and Lactobacillus rhamnosus, in displacing pre-formed biofilms of Escherichia coli and Staphylococcus aureus from medical-grade silicone. Single-species biofilms of 24 h were placed in contact with each probiotic suspension for 6 h and 24 h, and the reductions in biofilm cell culturability and total biomass were monitored by counting colony-forming units and crystal violet assay, respectively. Both probiotics significantly reduced the culturability of E. coli and S. aureus biofilms, mainly after 24 h of exposure, with reduction percentages of 70% and 77% for L. plantarum and 76% and 63% for L. rhamnosus, respectively. Additionally, the amount of E. coli biofilm determined by CV staining was maintained approximately constant after 6 h of probiotic contact and significantly reduced up to 67% after 24 h. For S. aureus, only L. rhamnosus caused a significant effect on biofilm amount after 6 h of treatment. Hence, this study demonstrated the potential of lactobacilli to control the development of pre-established uropathogenic biofilms.

Carvalho, Fábio M.↗
DOE OSTI2019

CT urography: how to optimize the technique

Purpose: Computed tomography urography (CTU) has emerged as the modality of choice for imaging the urinary tract within the past few decades. It is a powerful tool that enables detailed anatomic evaluation of the urinary tract in order to identify primary urothelial malignancies, benign urinary tract conditions, and associated abdominopelvic pathologies. As such, there have been extensive efforts to optimize CTU protocol. Methods: This article reviews the published literature on CTU protocol optimization, including contrast bolus timing, dose reduction, reconstruction algorithms, and ancillary practices. Conclusion: There have been many advances in CTU techniques, which allow for imaging diagnosis of a wide spectrum of diseases while minimizing radiation dose and maximizing urinary tract distension and opacification.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1986

The Central Nervous Connections Involved in the Vomiting Reflex

The vomiting reflex may be elicited by a number of different types or classes of stimuli involving many varieties of receptor structures and considerable diversity in afferent pathways and central connections. Central relay or mediating structures thus may vary widely according to the type of initial emetic stimulus. The emetic circuits which have been most completely delineated to date are probably those in which the Chemoreceptor Trigger Zone (CTZ) in the Area Postrema (AP) functions as a key mediating structure. Even in this system, however, there are large gaps in our knowledge of the nerve tracts and central nervous connections involved. Knowledge of most other emetic circuits subserving the emetic reflex resulting from many diverse types of stimuli such, for example, as emotional stress (e.g. psychogenic vomiting, Wruble et al. 1982), pain (e.g. testicular trauma), and chemical or mechanical irritation of the gastrointestinal tract or urinary tract is quite incomplete at this time, thus precluding any very adequate description of their central connections at present. One physiological system, however, which has received considerable attention recently in relation to the vomiting reflex elicited by motion stimuli is the vestibular system. Due to the paucity of data on central nervous connections of several or the non-vestibular types of emetic stimuli cited above, we will devote most of our attention in this brief review to the central connections of the vestibular system which seem likely to be involved in the vomiting response to motion stimuli. However, the latter part of the review will be concerned with the concept of the reticular vomiting centre in relation to the ParviCellular Reticular Formation (PCRF), and will thus probably pertain to all of the many classes of emetic stimuli since it will address the question of the final common emetic pathway.

Brizzee, K. R.↗
DOE OSTI2020

Tailoring a Global Iron Regulon to a Uropathogen

Pathogenicity islands and plasmids bear genes for pathogenesis of various Escherichia coli pathotypes. Although there is a basic understanding of the contribution of these virulence factors to disease, less is known about variation in regulatory networks in determining disease phenotypes. Here, we dissected a regulatory network directed by the conserved iron homeostasis regulator, ferric uptake regulator (Fur), in uropathogenic E. coli (UPEC) strain CFT073. Comparing anaerobic genome-scale Fur DNA binding with Fur-dependent transcript expression and protein levels of the uropathogen to that of commensal E. coli K-12 strain MG1655 showed that the Fur regulon of the core genome is conserved but also includes genes within the pathogenicity/genetic islands. Unexpectedly, regulons indicative of amino acid limitation and the general stress response were also indirectly activated in the uropathogen fur mutant, suggesting that induction of the Fur regulon increases amino acid demand. Using RpoS levels as a proxy, addition of amino acids mitigated the stress. In addition, iron chelation increased RpoS to the same levels as in the fur mutant. The increased amino acid demand of the fur mutant or iron chelated cells was exacerbated by aerobic conditions, which could be partly explained by the O 2 -dependent synthesis of the siderophore aerobactin, encoded by an operon within a pathogenicity island. Taken together, these data suggest that in the iron-poor environment of the urinary tract, amino acid availability could play a role in the proliferation of this uropathogen, particularly if there is sufficient O 2 to produce aerobactin. IMPORTANCE Host iron restriction is a common mechanism for limiting the growth of pathogens. We compared the regulatory network controlled by Fur in uropathogenic E. coli (UPEC) to that of nonpathogenic E. coli K-12 to uncover strategies that pathogenic bacteria use to overcome iron limitation. Although iron homeostasis functions were regulated by Fur in the uropathogen as expected, a surprising finding was the activation of the stringent and general stress responses in the uropathogen fur mutant, which was rescued by amino acid addition. This coordinated global response could be important in controlling growth and survival under nutrient-limiting conditions and during transitions from the nutrient-rich environment of the lower gastrointestinal (GI) tract to the more restrictive environment of the urinary tract. The coupling of the response of iron limitation to increased demand for amino acids could be a critical attribute that sets UPEC apart from other E. coli pathotypes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

What a difference a delay makes! CT urogram: a pictorial essay

Purpose: The aim of this pictorial essay is to demonstrate several cases where the diagnosis would have been difficult or impossible without the excretory phase image of CT urography. Methods: A brief discussion of CT urography technique and dose reduction is followed by several cases illustrating the utility of CT urography. Results: CT urography has become the primary imaging modality for evaluation of hematuria, as well as in the staging and surveillance of urinary tract malignancies. CT urography includes a non-contrast phase and contrast-enhanced nephrographic and excretory (delayed) phases. While the three phases add to the diagnostic ability of CT urography, it also adds potential patient radiation dose. Several techniques including automatic exposure control, iterative reconstruction algorithms, higher noise tolerance, and split-bolus have been successfully used to mitigate dose. The excretory phase is timed such that the excreted contrast opacifies the urinary collecting system and allows for greater detection of filling defects or other abnormalities. Sixteen cases illustrating the utility of excretory phase imaging are reviewed. Conclusions: Excretory phase imaging of CT urography can be an essential tool for detecting and appropriately characterizing urinary tract malignancies, renal papillary and medullary abnormalities, CT radiolucent stones, congenital abnormalities, certain chronic inflammatory conditions, and perinephric collections.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1987

Cutting Head for Ultrasonic Lithotripsy

Kidney stones lodged in urinary tract disintegrated with increased safety and efficiency by cutting head attached to end of vibrated wire probe. Aligns probe with stone and enables probe to vibrate long enough to disintegrate stone. Design of cutting head reduces risk of metal-fatigue-induced breakage of probe tip leaving metal fragments in urinary tract. Teeth of cutting head both seat and fragment kidney stone, while extension of collar into catheter lessens mechanical strain in probe wire, increasing probe life and lessening danger of in situ probe breakage.

Angulo, E. D.↗
NASA NTRS2002

Pathology effects at radiation doses below those causing increased mortality

Mortality data from experiments conducted at the Argonne National Laboratory (ANL) on the long-term effects of external whole-body irradiation on B6CF(1) mice were used to investigate radiation-induced effects at intermediate doses of (60)Co gamma rays or fission-spectrum neutrons either delivered as a single exposure or protracted over 60 once-weekly exposures. Kaplan-Meier analyses were used to identify the lowest dose in the ANL data (within radiation quality, pattern of exposure, and sex) at which radiation-induced mortality caused by primary tumors could be detected (approximately 1-2 Gy for gamma rays and 10-15 cGy for neutrons). Doses at and below these levels were then examined for radiation-induced shifts in the spectrum of pathology detected at death. To do this, specific pathology events were pooled into larger assemblages based on whether they were cancer, cardiovascular disease or non-neoplastic diseases detected within the lungs and pleura, liver and biliary tract, reproductive organs, or urinary tract. Cancer and cardiovascular disease were further subdivided into categories based on whether they caused death, contributed to death, or were simply observed at death. Counts of how often events falling within each of these combined pathology categories occurred within a mouse were then used as predictor variables in logistic regression to determine whether irradiated mice could be distinguished from control mice. Increased pathology burdens were detected in irradiated mice at doses lower than those causing detectable shifts in mortality-22 cGy for gamma rays and 2 cGy for neutrons. These findings suggest that (1) models based on mortality data alone may underestimate radiation effects, (2) radiation may have adverse health consequences (i.e. elevated health risks) even when mortality risks are not detected, and (3) radiation-induced pathologies other than cancer do occur, and they involve multiple organ systems.

Non-NASA Center↗
DOE OSTI2023

Organic Matrix Derived from Host–Microbe Interplay Contributes to Pathological Renal Biomineralization

Matrix stones are a rare form of kidney stones. They feature a high percentage of hydrogel-like organic matter, and their formation is closely associated with urinary tract infections. Herein, comprehensive materials and biochemical approaches were taken to map the organic-inorganic interface and gather insights into the host-microbe interplay in pathological renal biomineralization. Surgically extracted soft and slimy matrix stones were examined using micro-X-ray computed tomography and various microspectroscopy techniques. Higher-mineral-density laminae were positive for calcium-bound Alizarin red. Lower-mineral-density laminae revealed periodic acid-Schiff-positive organic filamentous networks of varied thickness. These organic filamentous networks, which featured a high polysaccharide content, were enriched with zinc, carbon, and sulfur elements. Neutrophil extracellular traps (NETs) along with immune response-related proteins, including calprotectin, myeloperoxidase, CD63, and CD86, also were identified in the filamentous networks. Expressions of NETs and upregulation of polysaccharide-rich mucin secretion are proposed as a part of the host immune defense to "trap" pathogens. These host-microbe derived organic matrices can facilitate heterogeneous nucleation and precipitation of inorganic particulates, resulting in macroscale aggregates known as "matrix stones". These insights into the plausible aggregation of constituents through host-microbe interplay underscore the unique "double-edged sword" effect of the host immune response to pathogens and the resulting renal biominerals.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

Protecting Space Travelers from Kidney Stones: Renal Stone Risk During Space Flight

Renal stones, popularly known as kidney or bladder stones, are small rock-like objects formed in the kidneys or urinary tract by deposits of calcium and other minerals. The problem arises when the stones block the drainage of the kidney, resulting in urinary obstruction and pain. Passing these stones can be one of the most painful experiences a person will endure so doctors often prescribe pain relievers to ease the experience. Drinking plenty of fluids, which help flush waste out of the body, and eating a well-balanced diet are the first steps to preventing stones. For individuals at risk, this may not be enough, and a doctor may recommend a special diet and medications. Unfortunately, approximately 60 percent of people who have had a renal stone will experience a recurrence. This is particularly true of men, who are four to five times more likely to develop stones than women. Renal stones do not discriminate based on age; even children are at risk. Astronauts are particularly at risk of developing renal stones because they lose bone and muscle mass; calcium, other minerals, and protein normally used for bone and muscle end up in the bloodstream and then in the kidneys. Without plenty of fluid to wash them away, crystals can form and then grow into stones. This factor compounds the risk for astronauts, since they also perceive that they are less thirsty in space and will drink less than normal during the mission. To minimize all of these factors, doctors must instead treat the stone-forming compounds with medication. This study will use potassium citrate to reduce the risk of stone formation. Renal stones are never convenient, but they are a particular concern for astronauts who have limited access to treatment during flight. Researchers are examining how earthbound preventions for renal stone formation work in flight, ensuring missions are not ended prematurely due to this medical condition. During STS-107, earthbound preventions and treatments become astronauts' gain.

Whitson, Peggy↗
NASA NTRS2016

NASA Astronaut Urinary Conditions Associated with Spaceflight

INTRODUCTION: Spaceflight is associated with many factors which may promote kidney stone formation, urinary retention, and/or Urinary Tract Infection (UTI). According to ISS mission predictions supplied by NASA's Integrated Medical Model, kidney stone is the second and sepsis (urosepsis as primary driver) the third most likely reason for emergent medical evacuation from the International Space Station (ISS). METHODS: Inflight and postflight medical records of NASA astronauts were reviewed for urinary retention, UTI and kidney stones during Mercury, Gemini, Apollo, Mir, Shuttle, and ISS expeditions 1-38. RESULTS: NASA astronauts have had 7 cases of kidney stones in the 12 months after flight. Three of these cases occurred within 90 to 180 days after landing and one of the seven cases occurred in the first 90 days after flight. There have been a total of 16 cases (0.018 events per person-flights) of urinary retention during flight. The event rates per mission are nearly identical between Shuttle and ISS flights (0.019 vs 0.021 events per person-flights). In 12 of the 16 cases, astronauts had taken at least one space motion sickness medication. Upon further analysis, it was determined that the odds of developing urinary retention in spaceflight is 3 times higher among astronauts who took promethazine. The female to male odds ratio for inflight urinary retention is 11:14. An astronaut with urinary retention is 25 times more likely to have a UTI with a 17% infection rate per mission. There have been 9 reported UTIs during spaceflight. DISCUSSION: It is unclear if spaceflight carries an increased post-flight risk of kidney stones. Regarding urinary retention, the female to male odds ratio is higher during flight compared to the general population where older males comprise almost all cases due to prostatic hypertrophy. This female prevalence in spaceflight is even more concerning given the fact that there have been many more males in space than females. Terrestrial medications with a known side effect of urinary retention are also associated with urinary retention during flight. However, not all cases of urinary retention surrounded medication use inflight. It is also known that UTI is a terrestrial cause of urinary retention. Furthermore, the treatment of urinary retention with a urinary catheter may be more likely to initiate a UTI in space than on the ground, as aseptic techniques can be particularly challenging with an inexperienced provider in a free-floating environment. Inflight urinary retention and UTI have proven to be highly associated and urinary risks should be considered collectively when planning for space flight.

Law, Jennifer↗
DOE OSTI2019

The application of cinematic rendering to CT evaluation of upper tract urothelial tumors: principles and practice

Upper tract urothelial carcinoma (UTUC) is a relatively uncommon but aggressive genitourinary malignancy for which multi-phase contrast-enhanced computed tomography (CT) plays an important role in evaluation and staging. 3D imaging with maximum intensity projection (MIP) and volume-rendered (VR) images has been described as a useful means of evaluating UTUC. In this study, we describe the technique of a novel 3D methodology known as cinematic rendering (CR) and provide clinical examples of UTUC visualized with CR. CR utilizes a complex universal lighting model in order to create photorealistic images with improved detail and depth in comparison to MIP or VR images. In the case of UTUC, CR can be used in different contrast phases to show abnormally thickened and enhancing urothelium or filling defects in the renal collecting system or ureters in the excretory phase. CR images can also be manipulated in order to generate translucent views of the upper urinary tract in order to add conspicuity to intraluminal findings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Design and Evaluation of Pyridinyl Sulfonyl Piperazine LpxH Inhibitors with Potent Antibiotic Activity Against Enterobacterales

Enterobacterales, a large order of Gram-negative bacteria, including Escherichia coli and Klebsiella pneumoniae, are major causes of urinary tract and gastrointestinal infections, pneumonia, and other diseases in healthcare settings and communities. ESBL-producing Enterobacterales and carbapenem-resistant Enterobacterales can break down commonly used antibiotics, with some strains being resistant to all available antibiotics. This public health threat necessitates the development of novel antibiotics, ideally targeting new pathways in these bacteria. Gram-negative bacteria possess an outer membrane enriched with lipid A, a saccharolipid that serves as the membrane anchor of lipopolysaccharides and the active component of the bacterial endotoxin, causing septic shock. The biosynthesis of lipid A is crucial for the viability of Gram-negative bacteria, and as an essential enzyme in this process, LpxH has emerged as a promising target for developing novel antibiotics against multidrugresistant Gram-negative pathogens. Here, we report the development of pyridinyl sulfonyl piperazine LpxH inhibitors. Among them, ortho-substituted pyridinyl compounds significantly boost LpxH inhibition and antibiotic activity over the original phenyl series. Structural and QM/MM analyses reveal that these improved activities are primarily due to the enhanced interaction between F141 of the LpxH insertion lid and the pyridinyl group. Incorporation of the N-methyl-N-phenyl-methanesulfonamide moiety into the pyridinyl sulfonyl piperazine backbone results in JHLPH- 106 and JH-LPH-107, both of which exhibit potent antibiotic activity against wild-type Enterobacterales such as K. pneumoniae and E. coli. JH-LPH-107 exhibits a low rate of spontaneous resistance and a high safety window in vitro, rendering it an excellent lead for further clinical development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

High-throughput methods leveraging robotics and computer vision for the development of therapeutic phage cocktails

We present the high-throughput automated screening techniques that are being used to develop bacteriophage-based therapeutic products currently under investigation in human clinical trials to combat urinary tract infections. By integrating modern liquid handling robotics, standardized phenotypic assays, and computer vision-based enumeration, we established a platform capable of reproducibly screening large collections of phages against clinically derived bacterial strain panels. This approach enabled systematic assessment of phage-bacteria interactions at scale, facilitating the identification and optimization of phage cocktails with broad in vitro activity. Although bacteriophage therapy has long been investigated as a strategy for treating bacterial infections, few frameworks exist for developing phage combinations in a reproducible and scalable manner. The methods outlined here address this gap and aim to support the broader development of therapeutic assets available to combat antibiotic resistance.

Penke, Taylor J. R. [Locus Biosciences, Morrisvill↗