Causal diagramming for assessing human system risk in spaceflight.

For over a decade, the National Aeronautics and Space Administration (NASA) has tracked and configuration-managed approximately 30 risks that affect astronaut health and performance before, during and after spaceflight. The Human System Risk Board (HSRB) at NASA Johnson Space Center is responsible for setting the official risk posture for each of the human system risks and determining-based on evaluation of the available evidence-when that risk posture changes. The ultimate purpose of tracking and researching these risks is to find ways to reduce spaceflight-induced risk to astronauts. The adverse effects of spaceflight begin at launch and continue throughout the duration of the mission, and in some cases, across the lifetime of the astronaut. Historically, research has been conducted in individual risk "silos" to characterize risk, however, astronauts are exposed to all risks simultaneously. In January of 2020, the HSRB at NASA began assessing the potential value of causal diagramming as a tool to facilitate understanding of the complex causes and effects that contribute to spaceflight-induced human system risk. Causal diagrams in the form of directed acyclic graphs (DAGs) are used to provide HSRB stakeholders with a shared mental model of the causal flow of risk. While primarily improving communication among those stakeholders, DAGs also allow a composite risk network to be created that can be tracked and configuration managed. This paper outlines the HSRB's pilot process for this effort, the lessons learned, and future goals for data-driven risk management approaches.

Levels of evidence for human system risk evaluation.

NASA uses a continuous risk management process to seek out new knowledge of spaceflight-induced risk to human health and performance. The evidence base that informs the risk assessments in this domain is constantly changing as more information is gleaned from a continuous human presence in space and from ongoing research. However, the limitations of this evidence are difficult to characterize because fewer than 700 humans have ever flown in space, and information comes from a variety of sources that span disciplines, including engineering, medicine, food and nutrition, and many other life sciences. The Human System Risk Board (HSRB) at NASA is responsible for assessing risk to astronauts and communicating this risk to agency decision-makers. A critical part of that communication is conveying the uncertainty regarding the understanding of the changes that spaceflight induces in human processes and the complex interactions between humans and the spacecraft. Although the strength of evidence grades is common in the academic literature, these scores are often not useful for the problems of human spaceflight. The HSRB continues to update the processes used to report the levels of evidence. This paper describes recent updates to the methods used to assign the level of evidence scores to the official risk postures and to the causal diagrams used by the HSRB.

ART2Dose: A comprehensive dose verification platform for online adaptive radiotherapy.

BACKGROUND: Online adaptive radiotherapy (ART) involves the development of adaptable treatment plans that consider patient anatomical data obtained right prior to treatment administration, facilitated by cone-beam computed tomography guided adaptive radiotherapy (CTgART) and magnetic resonance image-guided adaptive radiotherapy (MRgART). To ensure accuracy of these adaptive plans, it is crucial to conduct calculation-based checks and independent verification of volumetric dose distribution, as measurement-based checks are not practical within online workflows. However, the absence of comprehensive, efficient, and highly integrated commercial software for secondary dose verification can impede the time-sensitive nature of online ART procedures. PURPOSE: The main aim of this study is to introduce an efficient online quality assurance (QA) platform for online ART, and subsequently evaluate it on Ethos and Unity treatment delivery systems in our clinic. METHODS: To enhance efficiency and ensure compliance with safety standards in online ART, ART2Dose, a secondary dose verification software, has been developed and integrated into our online QA workflow. This implementation spans all online ART treatments at our institution. The ART2Dose infrastructure comprises four key components: an SQLite database, a dose calculation server, a report generator, and a web portal. Through this infrastructure, file transfer, dose calculation, report generation, and report approval/archival are seamlessly managed, minimizing the need for user input when exporting RT DICOM files and approving the generated QA report. ART2Dose was compared with Mobius3D in pre-clinical evaluations on secondary dose verification for 40 adaptive plans. Additionally, a retrospective investigation was conducted utilizing 1302 CTgART fractions from ten treatment sites and 1278 MRgART fractions from seven treatment sites to evaluate the practical accuracy and efficiency of ART2Dose in routine clinical use. RESULTS: With dedicated infrastructure and an integrated workflow, ART2Dose achieved gamma passing rates that were comparable to or higher than those of Mobius3D. Additionally, it significantly reduced the time required to complete pre-treatment checks by 3-4 min for each plan. In the retrospective analysis of clinical CTgART and MRgART fractions, ART2Dose demonstrated average gamma passing rates of 99.61 ± 0.83% and 97.75 ± 2.54%, respectively, using the 3%/2 mm criteria for region greater than 10% of prescription dose. The average calculation times for CTgART and MRgART were approximately 1 and 2 min, respectively. CONCLUSION: Overall, the streamlined implementation of ART2Dose notably enhances the online ART workflow, offering reliable and efficient online QA while reducing time pressure in the clinic and minimizing labor-intensive work.

Targeted degrader technologies as prospective SARS-CoV-2 therapies.

COVID-19 remains a severe public health threat despite the WHO declaring an end to the public health emergency in May 2023. Continual development of SARS-CoV-2 variants with resistance to vaccine-induced or natural immunity necessitates constant vigilance as well as new vaccines and therapeutics. Targeted protein degradation (TPD) remains relatively untapped in antiviral drug discovery and holds the promise of attenuating viral resistance development. From a unique structural design perspective, this review covers antiviral degrader merits and challenges by highlighting key coronavirus protein targets and their co-crystal structures, specifically illustrating how TPD strategies can refine existing SARS-CoV-2 3CL protease inhibitors to potentially produce superior protease-degrading agents.

Updates to the NASA human system risk management process for space exploration.

This paper describes updates to NASA's approach for assessing and mitigating spaceflight-induced risks to human health and performance. This approach continues to evolve to meet dynamically changing risk environments: lunar missions are currently being designed and the ultimate destination will be Mars. Understanding the risks that astronauts will face during a Mars mission will depend on building an evidence base that informs not only how the humans respond to the challenges of the spaceflight environment, but also how systems and vehicles can be designed to support human capabilities and limitations. This publication documents updates to the risk management process used by the Human System Risk Board at NASA and includes changes to the likelihood and consequence matrix used by the board, the design reference mission categories and parameters, and the standardized evaluation of the levels of evidence that the board accepts when setting risk posture. Causal diagramming, using directed acyclic graphs, provides all stakeholders with the current understanding of how each risk proceeds from a spaceflight hazard to a mission-level outcome. This standardized approach enables improved communication among stakeholders and delineates how and where more knowledge can improve perspective of human system risks and which countermeasures can best mitigate these risks.

Evaluation of fan-beam kilovoltage computed tomography image quality on a novel biological-guided radiotherapy platform.

Background and Purpose: A recently developed biology-guided radiotherapy platform, equipped with positron emission tomography (PET) and computed tomography (CT), provides both anatomical and functional image guidance for radiotherapy. This study aimed to characterize performance of the kilovoltage CT (kVCT) system on this platform using standard quality metrics measured on phantom and patient images, using CT simulator images as reference. Materials and Methods: Image quality metrics, including spatial resolution/modular transfer function (MTF), slice sensitivity profile (SSP), noise performance and image uniformity, contrast-noise ratio (CNR) and low-contrast resolution, geometric accuracy, and CT number (HU) accuracy, were evaluated on phantom images. Patient images were evaluated mainly qualitatively. Results: On phantom images the MTF10% is about 0.68 lp/mm for kVCT in PET/CT Linac. The SSP agreed with nominal slice thickness within 0.7 mm. The diameter of the smallest visible target (1% contrast) is about 5 mm using medium dose mode. The image uniformity is within 2.0 HU. The geometric accuracy tests passed within 0.5 mm. Relative to CT simulator images, the noise is generally higher and the CNR is lower in PET/CT Linac kVCT images. The CT number accuracy is comparable between the two systems with maximum deviation from the phantom manufacturer range within 25 HU. On patient images, higher spatial resolution and image noise are observed on PET/CT Linac kVCT images. Conclusions: Major image quality metrics of the PET/CT Linac kVCT were within vendor-recommended tolerances. Better spatial resolution but higher noise and better/comparable low contrast visibility were observed as compared to a CT simulator when images were acquired with clinical protocols.

Viability of internal comparisons for epidemiological research in the US astronaut corps.

This study aims to determine whether astronauts who have not flown in space can provide an unbiased comparison to astronauts who have flown in space when analyzing long-term health outcomes such as incidence of chronic disease and mortality. Various propensity score methods failed to achieve good balance between groups, demonstrating that even with sophisticated rebalancing methods the group of non-flight astronauts cannot be demonstrated to be an unbiased comparison group for examining the effect of the hazards of spaceflight on incidence and mortality from chronic diseases.

A Structured Process to Identify Fit-for-Purpose Study Design and Data to Generate Valid and Transparent Real-World Evidence for Regulatory Uses.

Generating evidence from real-world data requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD)-intended to be used together-provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data. In this update (referred to as "SPIFD2" to encompass both the design and data aspects) we provide an update to these frameworks that combines the templates into one, more explicitly calls for articulation of the hypothetical target trial and sources of bias that may arise in the real-world emulation, and provides explicit references to the Structured Template and Reporting Tool for Real-World Evidence (STaRT-RWE) tables that we suggest using immediately after invoking the SPIFD2 framework. Following the steps recommended in the SPIFD2 process requires due diligence on the part of the researcher to ensure that every aspect of study design and data selection is rationalized and supported by evidence. The resulting stepwise documentation enables reproducibility and clear communication with decision makers, and it increases the likelihood that the evidence generated is valid, fit-for-purpose, and sufficient to support healthcare and regulatory decisions.

Chebyshev series: Derivation and evaluation.

In this paper we use a contour integral method to derive a bilateral generating function in the form of a double series involving Chebyshev polynomials expressed in terms of the incomplete gamma function. Generating functions for the Chebyshev polynomial are also derived and summarized. Special cases are evaluated in terms of composite forms of both Chebyshev polynomials and the incomplete gamma function.

Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats.

The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac's antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of ß-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy.

Chemoselective Oxidation of Thiols with Oxoammonium Cations.

The oxidation of various aryl and aliphatic thiols with the commercially available and environmentally benign reagent Bobbitt's salt (1) has been investigated. The reaction affords the corresponding disulfide products in good to excellent yields (71-99%) and can be accomplished in water, methanol, or acetonitrile solvent. Moreover, the process is highly chemoselective, tolerating traditionally oxidation-labile groups such as free amines and alcohols. Combined experimental and computational studies reveal that the oxidation takes place via a polar two-electron process with concomitant and unexpected deoxygenation of the oxoammonium cation through homolysis of the weak N-O bond, differing from prototypical radical-based thiol couplings. This unusual consumption of the oxidant has significant implications for the development of new nitroxide-based radical traps for probing S-centered radicals, the advancement of new electrochemical or catalytic processes involving nitroxide/oxoammonium salt redox couples, and applications to biological systems.

Machine characterization and central axis depth dose data of a superficial x-ray radiotherapy unit.

Objectives. The purpose of this study is to present data from the clinical commissioning of an Xstrahl 150 x-ray unit used for superficial radiotherapy,Methods. Commissioning tasks included vendor acceptance tests, timer reproducibility, linearity and end-effect measurements, half-value layer (HVL) measurements, inverse square law verification, head-leakage measurements, and beam output calibration. In addition, percent depth dose (PDD) curves were determined for different combinations of filter/kV settings and applicators. Automated PDD water phantom scans were performed utilizing four contemporary detectors: a microDiamond detector, a microSilicon detector, an EDGE detector, and a PinPoint ionization chamber. The measured PDD data were compared to the published values in BJR Supplement 25,Results. The x-ray unit's mechanical, safety, and radiation characteristics were within vendor-stated specifications. Across sixty commissioned x-ray beams, the PDDs determined in water using solid state detectors were in excellent agreement with the BJR 25 data. For the lower (<100 kVp) and medium-energy (≥100 kVp) superficial beams the average agreement was within [-3.6,+0.4]% and [-3.7,+1.4]% range, respectively. For the high-energy superficial (low-energy orthovoltage) x-rays at 150 kVp, the average difference for the largest 20 × 20 cm2collimator was (-0.7 ± 1.0)%,Conclusions. This study presents machine characterization data collected for clinical use of a superficial x-ray unit. Special focus was placed on utilizing contemporary detectors and techniques for the relative PDD measurements using a motorized water phantom. The results in this study confirm that the aggregate values published in the BJR 25 report still serve as a valid benchmark when comparing data from site-specific measurements, or the reference data for clinical utilization without such measurements,Advances in knowledge. This paper presents comprehensive data from the acceptance and commissioning of a modern kilovoltage superficial x-ray radiotherapy machine. Comparisons between the PDD data measured in this study using different detectors and BJR 25 data are highlighted.

Extended Wang sum and associated products.

The Wang sum involving the exponential sums of Lerch's Zeta functions is extended to the finite sum of the Huwitz-Lerch Zeta function to derive sums and products involving cosine and tangent trigonometric functions. The general theorem used to derive these sums and products is in the form of the finite sum over positive integers of the Hurwitz-Lerch Zeta function where the associated parameters are general complex numbers. New Hurwitz-Lerch Zeta function recurrence identities with consecutive neighbours are derived. Some finite sum and product formulae examples involving cosine, tangent and the product of cosine and tangent functions are also derived and evaluated.

Validating Causal Diagrams of Human Health Risks for Spaceflight: An Example Using Bone Data from Rodents.

As part of the risk management plan for human system risks at the US National Aeronautics and Space Administration (NASA), the NASA Human Systems Risk Board uses causal diagrams (in the form of directed, acyclic graphs, or DAGs) to communicate the complex web of events that leads from exposure to the spaceflight environment to performance and health outcomes. However, the use of DAGs in this way is relatively new at NASA, and thus far, no method has been articulated for testing their veracity using empirical data. In this paper, we demonstrate a set of procedures for doing so, using (a) a DAG related to the risk of bone fracture after exposure to spaceflight; and (b) four datasets originally generated to investigate this phenomenon in rodents. Tests of expected marginal correlation and conditional independencies derived from the DAG indicate that the rodent data largely agree with the structure of the diagram. Incongruencies between tests and the expected relationships in one of the datasets are likely explained by inadequate representation of a key DAG variable in the dataset. Future directions include greater tie-in with human data sources, including multiomics data, which may allow for more robust characterization and measurement of DAG variables.

Dewlap colour variation in Anolis sagrei is maintained among habitats within islands of the West Indies.

Animal signals evolve in an ecological context. Locally adapting animal sexual signals can be especially important for initiating or reinforcing reproductive isolation during the early stages of speciation. Previous studies have demonstrated that dewlap colour in Anolis lizards can be highly variable between populations in relation to both biotic and abiotic adaptive drivers at relatively large geographical scales. Here, we investigated differentiation of dewlap coloration among habitat types at a small spatial scale, within multiple islands of the West Indies, to test the hypothesis that similar local adaptive processes occur over smaller spatial scales. We explored variation in dewlap coloration in the most widespread species of anole, Anolis sagrei, across three characteristic habitats spanning the Bahamas and the Cayman Islands, namely beach scrub, primary coppice forest and mangrove forest. Using reflectance spectrometry paired with supervised machine learning, we found significant differences in spectral properties of the dewlap between habitats within small islands, sometimes over very short distances. Passive divergence in dewlap phenotype associated with isolation-by-distance did not seem to explain our results. On the other hand, these habitat-specific dewlap differences varied in magnitude and direction across islands, and thus, our primary test for adaptation-parallel responses across islands-was not supported. We suggest that neutral processes or selection could be involved in several ways, including sexual selection. Our results shed new light on the scale at which signal colour polymorphism can be maintained in the presence of gene flow, and the relative role of local adaptation and other processes in driving these patterns of dewlap colour variation across islands.

The Structured Process to Identify Fit-For-Purpose Data: A Data Feasibility Assessment Framework.

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions. Used with the SPACE framework, the Structured Process to Identify Fit-For-Purpose Data (SPIFD) provides a systematic process for conducting feasibility assessments to determine if a data source is fit for decision making, helping ensure justification and transparency throughout study development, from articulation of a specific and meaningful research question to identification of fit-for-purpose data and study design.

Volumetric Modulated Arc Therapy Enabled Total Body Irradiation (VMAT-TBI): Six-year Clinical Experience and Treatment Outcomes.

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage >90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were <100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.

Integration of Real-World Data and Genetics to Support Target Identification and Validation.

Even modest improvements in the probability of success of selecting drug targets which are ultimately approved can substantially reduce the costs of research and development. Drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. A key enabler of identifying and validating these genetically validated targets is access to association results from genome-wide genotyping, whole-exome sequencing, and whole-genome sequencing studies with observable traits (often diseases) across large numbers of individuals. Today, linkage between genotype and real-world data (RWD) provides significant opportunities to not only increase the statistical power of genome-wide association studies by ascertaining additional cases for diseases of interest, but also to improve diversity and coverage of association studies across the disease phenome. As RWD-genetics linked resources continue to grow in diversity of participants, breadth of data captured, length of observation, and number of participants, there is a greater need to leverage the experience of RWD experts, clinicians, and highly experienced geneticists together to understand which lessons and frameworks from general research using RWD sources are relevant to improve genetics-driven drug discovery and development. This paper describes new challenges and opportunities for phenotypes enabled by diverse RWD sources, considerations in the use of RWD phenotypes for disease gene identification across the disease phenome, and challenges and opportunities in leveraging RWD phenotypes in target validation. The paper concludes with views on the future directions for phenotype development using RWD, and key questions requiring further research and development to advance this nascent field.