Validation of the prognostic index for spine metastasis (PRISM) for stratifying survival in patients treated with spinal stereotactic body radiation.

PURPOSE: The Prognostic Index for Spinal Metastasis (PRISM) is a scoring system derived from prospective data from a single institution that stratifies patients undergoing spine stereotactic radiosurgery (SSRS) for spinal metastases into subgroups by overall (OS). We sought to further demonstrate its generalizability by performing validation with a large dataset from a second high-volume institution, Mayo Clinic. METHODS AND MATERIALS: Eight hundred seventy-nine patients-424 from Mayo Clinic and 455 from MD Anderson Cancer Center (MDACC)-who received SSRS between 2007 and 2019 were identified. Patients were stratified by PRISM criteria, and overall survival (OS) for the PRISM groups for each cohort was compared using Kaplan-Meier estimations and univariate Cox proportional analyses. Model calibration and concordance indices (C-indices) were calculated for each cohort to assess the quality of the scoring system. RESULTS: Patient and tumor characteristics varied significantly between both cohorts including histology, sex, performance status, and number of organs involved (all P < 0.001). Median OS was 30.3 and 22.1 months for the Mayo and MDACC cohorts, respectively. Kaplan-Meier survival curves revealed robust separation between prognostic groups within both cohorts. The Mayo cohort showed median OS of 57.1, 37.0, 23.7, and 8.8 months for Groups 1, 2, 3, and 4, respectively. Univariate analysis revealed hazard ratios of 3.0 (95 % confidence interval [CI], 1.9-4.9), 5.2 (95 % CI, 3.2-8.3), and 12.9 (95 % CI, 7.8-21.4) for groups 2, 3 and 4, respectively all P < 0.001). The C-indices were 0.69 and 0.66 for the unstratified and stratified scores for the Mayo cohort, and 0.70 and 0.68 for the MDACC cohort, respectively. CONCLUSION: These data demonstrate robust validation of the PRISM score to stratify OS in patients treated with SSRS by a large external cohort, despite substantial differences among the cohorts. Overall, the PRISM scoring may help guide optimal treatment selection for patients with spine metastases.

Lung-Kidney Axis in Cystic Fibrosis: Early Urinary Markers of Kidney Injury Correlate with Neutrophil Activation and Worse Lung Function.

Background: Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF. Methods: Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in CF (n = 48) and healthy (n = 33) cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies. Results: PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and decreased lung function was most prominent in patients harboring chronic Pseudomonas aeruginosa infection. Conclusions: Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high Pseudomonas aeruginosa burden suggests that pulmonary disease may contribute to renal injury in CF.

New Processes for Ionizing Nonvolatile Compounds in Mass Spectrometry: The Road of Discovery to Current State-of-the-Art.

This Perspective covers discovery and mechanistic aspects as well as initial applications of novel ionization processes for use in mass spectrometry that guided us in a series of subsequent discoveries, instrument developments, and commercialization. Vacuum matrix-assisted ionization on an intermediate pressure matrix-assisted laser desorption/ionization source without the use of a laser, high voltages, or any other added energy was simply unbelievable, at first. Individually and as a whole, the various discoveries and inventions started to paint, inter alia, an exciting new picture and outlook in mass spectrometry from which key developments grew that were at the time unimaginable, and continue to surprise us in its simplistic preeminence. We, and others, have demonstrated exceptional analytical utility. Our current research is focused on how best to understand, improve, and use these novel ionization processes through dedicated platforms and source developments. These ionization processes convert volatile and nonvolatile compounds from solid or liquid matrixes into gas-phase ions for analysis by mass spectrometry using, e.g., mass-selected fragmentation and ion mobility spectrometry to provide accurate, and sometimes improved, mass and drift time resolution. The combination of research and discoveries demonstrated multiple advantages of the new ionization processes and established the basis of the successes that lead to the Biemann Medal and this Perspective. How the new ionization processes relate to traditional ionization is also presented, as well as how these technologies can be utilized in tandem through instrument modification and implementation to increase coverage of complex materials through complementary strengths.

Reconsidering Public Attitudes Toward Deceased Organ Donation Registration.

Background: The aim of the current study is to understand Americans' attitudes toward deceased organ donation and to assess their level of acceptance on positions toward organ donation. Methods: In summer and winter of 2023, 2 national samples completed measures of attitudes toward donation, reported their registration status, rated positions related to donation, and provided demographic information. Results: Data from 2 samples indicated registration estimates between 50% and 57% and a significant proportion of those unregistered reported reluctance to register. The believability of national registry estimates and ratings of acceptability of 9 organ donation positions differed by registration status. Conclusion: Mass media and motor vehicles interventions seeking to increase registration rates should take into consideration individual attitudes and support toward donation may not be as strong as once thought.

Increased hydrophilicity of lignin-derivable vs. bisphenol-based polysulfones for potential water filtration applications.

The functionality inherent in lignin-derivable aromatics (e.g., polar methoxy groups) can provide a potential opportunity to improve the hydrophilicity of polysulfones (PSfs) without the need for the additional processing steps and harsh reagents/conditions that are typically used in conventional PSf modifications. As determined herein, lignin-derivable PSfs without any post-polymerization modification exhibited higher hydrophilicity than comparable petroleum-based PSfs (commercial/laboratory-synthesized) and also demonstrated similar hydrophilicity to functionalized BPA-PSfs reported in the literature. Importantly, the lignin-derivable PSfs displayed improved thermal properties relative to functionalized BPA-PSfs in the literature, and the thermal properties of these bio-derivable PSfs were close to those of common non-functionalized PSfs. In particular, the glass transition temperature (T g) and degradation temperature of 5% weight loss (T d5%) of lignin-derivable PSfs (T g ∼165-170 °C, T d5% ∼400-425 °C) were significantly higher than those of typical functionalized BPA-PSfs in the literature (T g ∼110-160 °C, T d5% ∼240-260 °C) and close to those of unmodified, commercial/laboratory-synthesized BPA-/bisphenol F-PSfs (T g ∼180-185 °C, T d5% ∼420-510 °C).

Refinement of machine learning arterial waveform models for predicting blood loss in canines.

Introduction: Hemorrhage remains a leading cause of death in civilian and military trauma. Hemorrhages also extend to military working dogs, who can experience injuries similar to those of the humans they work alongside. Unfortunately, current physiological monitoring is often inadequate for early detection of hemorrhage. Here, we evaluate if features extracted from the arterial waveform can allow for early hemorrhage prediction and improved intervention in canines. Methods: In this effort, we extracted more than 1,900 features from an arterial waveform in canine hemorrhage datasets prior to hemorrhage, during hemorrhage, and during a shock hold period. Different features were used as input to decision tree machine learning (ML) model architectures to track three model predictors-total blood loss volume, estimated percent blood loss, and area under the time versus hemorrhaged blood volume curve. Results: ML models were successfully developed for total and estimated percent blood loss, with the total blood loss having a higher correlation coefficient. The area predictors were unsuccessful at being directly predicted by decision tree ML models but could be calculated indirectly from the ML prediction models for blood loss. Overall, the area under the hemorrhage curve had the highest sensitivity for detecting hemorrhage at approximately 4 min after hemorrhage onset, compared to more than 45 min before detection based on mean arterial pressure. Conclusion: ML methods successfully tracked hemorrhage and provided earlier prediction in canines, potentially improving hemorrhage detection and objectifying triage for veterinary medicine. Further, its use can potentially be extended to human use with proper training datasets.

Safety protocols, precautions, and countermeasures aboard the International Space Station (ISS) to prevent ocular injury.

The International Space Station (ISS) is a $100 billion epicenter of human activity in the vacuum of space, displaying mankind's collective endeavor to explore the cosmic frontier. Even within the marvels of technological sophistication aboard the ISS, the human eye remains a highly vulnerable structure. In the absence of multiple layers of protection and risk assessments, crewmembers would face a substantial increase in vulnerability to ocular injury. Aside from stringent preflight screening criteria for astronauts, the ISS is equipped with ophthalmic medications, environmental control and life support systems (e.g., humidity regulation, carbon dioxide removal, pressurized device regulators), and radiation protection to reduce ocular injury. Moreover, additional countermeasures are currently being developed to mitigate the effects of spaceflight-associated neuro-ocular syndrome (SANS) and lunar dust toxicity for the Artemis Program missions. The success of future endeavors hinges not only on continued technological innovation, but also respecting the intricate interplay between human physiology and the extraterrestrial environments. Establishing habitations on the Moon and Mars, as well as NASA's Gateway Program (humanity's first space station around the Moon), will introduce a new set of challenges, underscoring the necessity for continuous insights into ocular health in space. We discuss the safety protocols, precautions, and countermeasures implemented on the ISS to prevent ocular injury - an aspect often overshadowed by the grandeur of space exploration.

Development of an Intervention Targeted to Patients with Cancers Not Typically Perceived as Smoking-Related.

Smoking by cancer patients impairs treatment outcomes and prognoses across cancer types. Previous research shows greater smoking cessation motivation and quit rates among patients with cancers strongly linked to smoking (i.e., thoracic, head and neck) compared to other cancer types (e.g., melanoma). Therefore, there is a need to increase cessation motivation among patients with malignancies less commonly associated with smoking. Yet, no targeted educational materials exist to meet this information gap. This manuscript describes the development of theory-based self-help educational materials, targeted by cancer type, to increase motivation to quit smoking among patients with cancers not widely perceived as smoking-related (i.e., breast, melanoma, bladder, colorectal, gynecological). Using a three-phase iterative process, we first conducted in-depth interviews with our intended audience (N = 18) to identify information needs and nuanced content. Themes included patients' low knowledge about the connection between smoking and cancer etiology and outcomes; negative affect, habit, dependence, and weight gain as quitting barriers; and a preference for positive and non-judgmental content. Second, content creation was based on interview findings, the scientific literature, and framed following the teachable moment model. Last, learner verification and revisions via interviews with 22 patients assessed suitability of draft materials, with generally favorable responses. Resulting edits included tailoring cost savings to the cancer context, explaining cessation medications, and increasing appeal by improving the diversity (e.g., race) of the individuals in the photographs. The final booklets are low cost, easy to disseminate, and-pending efficacy studies-may expand smoking cessation to a wider spectrum of cancer patients.

Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial.

BACKGROUND AND AIMS: The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. This study addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) without attaining thresholds of LVEF. METHODS: Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (age 59±13 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS and 3D echocardiography were tracked over 12 months. A total of 105 patients (age 59±13 years, 75% women, 69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) between cardioprotection with neurohormonal antagonists versus usual care were randomized. The primary endpoint was 12-month change in MRI-LVEF; the secondary endpoint was MRI LVEF-defined CTRCD. RESULTS: During follow-up, 2 patients died and 2 developed heart failure. Most patients were randomized at 3 months (62%). Median doses of angiotensin inhibition/blockade and beta-blockade were 75% and 50% of respective targets; 21 (43%) had side-effects attributed to cardioprotection. Due to a smaller LVEF change from baseline with cardioprotection than usual care (-2.5±5.4% vs -5.6±5.9%, p=0.009), follow-up LVEF was higher after cardioprotection (59±5% vs 55±6%, p<0.0001). After adjustment for baseline LVEF, the mean (95% confidence interval) difference in the change in LVEF between the two groups was -3.6% (-1.8% to -5.5%, p<0.001). After cardioprotection, 1/49 patients developed 12-month LVEF-CTRCD, compared to 6/56 in usual care (p=0.075). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. CONCLUSIONS: In patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care.

Cardiac Function and Functional Capacity in Patients with Long COVID: a Comparison to Propensity-Matched Community Controls.

BACKGROUND: Cardiac impairment has been associated with acute COVID-19 since the earliest reports of the pandemic. However, its role in post-acute sequelae of COVID-19 (PASC, or "long COVID") is undefined, and many existing observations about cardiovascular involvement in PASC are uncontrolled. OBJECTIVE: To compare the prevalence of cardiac dysfunction in patients with Long COVID, and non-infected controls from the same community, and explore their association with functional capacity. METHODS: Echocardiography was used to assess cardiac structure and function, including the measurement of global longitudinal strain (GLS), in 190 participants with Long COVID. All underwent assessment of functional impairment by subjective (Duke Activity Status Index, DASI) and objective tests (6-minute walk test, 6MWT). The 190 participants from the Long COVID group were matched with those from 979 patients who underwent the same tests in the pre-COVID-19 era, using a propensity score. RESULTS: The 190 patients with Long COVID had similar age and risk factor profiles to those of their matched controls. LV dimensions and geometry, but not diastolic parameters, were significantly altered in the Long COVID group. The Long COVID group had subclinical systolic dysfunction (GLS 18.5±2.6 vs 19.3±2.7%, p=0.005), and more Long COVID patients had abnormal (<16%) GLS (13% vs 8%, p=0.035). The association of Long COVID with abnormal GLS (OR 1.49 [1.04, 2.45]) was independent of - and had a similar or greater effect size - than age and risk factors. There was no interaction of Long COVID with the association of risk factors with GLS. As expected, the Long COVID group had significant subjective (<85% predicted METS; 72% vs 5%, p<0.001) and objective functional impairment (29% vs 24%, p=0.026), but GLS was only weakly associated with both subjective (r=0.30, p=0.005) and objective (r=0.21, p=0.05) functional impairment. The presence of Long COVID was independently associated with subjective (OR=159.7 [95% CI: 61.6-414.2]), and objective functional impairment (OR=2.8 [95% CI: 1.5-5.2]). CONCLUSIONS: Impaired GLS and LV dimensions are the echocardiographic features that are over-represented in Long COVID, and this association is similar to, and independent of other risk factors. Impaired GLS is weakly associated with functional impairment.

A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis.

Introduction: Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. Methods: We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. Results: The mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma. Conclusion: Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.

Thin-film freeze-drying of an influenza virus hemagglutinin mRNA vaccine in unilamellar lipid nanoparticles with blebs.

Messenger RNA (mRNA) vaccines have revolutionized the fight against infectious diseases and are poised to transform other therapeutic areas. Lipid nanoparticles (LNP) represent the most successful delivery system for mRNA. While the mRNA-LNP products currently in clinics are stored as frozen suspensions, there is evidence that freeze-drying mRNA-LNP into dry powders can potentially enable their storage and handling at non-freezing temperatures. Previously, we successfully applied thin-film freeze-drying (TFFD) to transform a polyadenylic acid [poly(A)]-LNP formulation from a liquid suspension to dry powders. The poly(A)-LNP were structurally multilamellar spheres without blebs, but the mRNA vaccines in clinics are comprised of mRNA-LNP that are structurally spheres surrounded by a unilamellar lipid bilayer, with some containing blebs, and it was reported that the presence of blebs increases the sensitivity of mRNA-LNP to freeze-drying-induced stress. In the present study, using an influenza A virus hemagglutinin (HA) mRNA in LNP that were structurally similar to that in the COVID-19 mRNA vaccines currently in clinic, we studied the effect of TFFD on the physical properties, internal structure, as well as immunogenicity of the HA mRNA-LNP vaccine. We concluded that TFFD can be utilized to prepare dry powders of the HA mRNA-LNP, but a sufficient amount of excipients were needed to minimize changes in the physical properties, structure, and immunogenicity of the HA mRNA-LNP vaccine.

Nontargeted Lipidomics of Sorghum Grain Reveals Novel Fatty Acid Esters of Hydroxy Fatty Acids and Cultivar Differences in Lipid Profiles.

Sorghum, a globally grown gluten-free cereal, is used mainly as an animal feed in developed countries regardless of its potential for human consumption. In this study, we utilized nontargeted lipidomics to thoroughly analyze, compare, and characterize whole-grain lipids in six sorghum cultivars (cv) grown in a single field trial in Australia: Buster, Bazley, Cracker, Liberty, MR43, and Tiger. In total, 194 lipid molecular species representing five major lipid classes were identified. Multivariate analysis unveiled distinct lipid profiles among the cultivars. The most distinct lipid profile belonged to cv. MR43. The lower ω-6 to ω-3 ratio and optimal P/S ratio in cv. Bazley reflect this as a valuable source of balanced essential fatty acids in the diet. The novel bioactive lipids known as FAHFAs (fatty acid esters of hydroxy fatty acids) were identified and characterized in sorghum grains. These findings further emphasize the potential of whole-grain sorghum as a basis for new health-promoting food products.

Effect of hearing intervention on communicative function: A secondary analysis of the ACHIEVE randomized controlled trial.

BACKGROUND: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study was designed to determine the effects of a best-practice hearing intervention on cognitive decline among community-dwelling older adults. Here, we conducted a secondary analysis of the ACHIEVE Study to investigate the effect of hearing intervention on self-reported communicative function. METHODS: The ACHIEVE Study is a parallel-group, unmasked, randomized controlled trial of adults aged 70-84 years with untreated mild-to-moderate hearing loss and without substantial cognitive impairment. Participants were randomly assigned (1:1) to a hearing intervention (audiological counseling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed semiannually for 3 years. Self-reported communicative function was measured with the Hearing Handicap Inventory-Elderly Screening version (HHIE-S, range 0-40, higher scores indicate greater impairment). Effect of hearing intervention versus control on HHIE-S was analyzed through an intention-to-treat model controlling for known covariates. RESULTS: HHIE-S improved after 6-months with hearing intervention compared to control, and continued to be better through 3-year follow-up. We estimated a difference of -8.9 (95% CI: -10.4, -7.5) points between intervention and control groups in change in HHIE-S score from baseline to 6 months, -9.3 (95% CI: -10.8, -7.9) to Year 1, -8.4 (95% CI: -9.8, -6.9) to Year 2, and - 9.5 (95% CI: -11.0, -8.0) to Year 3. Other prespecified sensitivity analyses that varied analytical parameters did not change the observed results. CONCLUSIONS: Hearing intervention improved self-reported communicative function compared to a control intervention within 6 months and with effects sustained through 3 years. These findings suggest that clinical recommendations for older adults with hearing loss should encourage hearing intervention that could benefit communicative function and potentially have positive downstream effects on other aspects of health.

An Environmentally Stable, Biocompatible, and Multilayered Wound Dressing Film with Reversible and Strong Adhesion.

Reversible adhesives for wound care improve patient experiences by permitting reuse and minimizing further tissue injury. Existing reversible bandages are vulnerable to water and can undergo unwanted deformation during removal and readdressing procedures. Here, a biocompatible, multilayered, reversible wound dressing film that conforms to skin and is waterproof is designed. The inner layer is capable of instant adhesion to various substrates upon activation of the dynamic boronic ester bonds by water; intermediate hydrogel layer and outer silicone backing layer can enhance the dressing's elasticity and load distribution for adhesion, and the silicone outer layer protects the dressing from exposure to water. The adhesive layer is found to be biocompatible with mouse skin. Skin injuries on the mouse skin heal more rapidly with the film compared to no dressing controls. Evaluations of the film on skin of freshly euthanized minipigs corroborate the findings in the mouse model. The film remains attached to skins without delamination despite subjecting to various degrees of deformation. Exposure to water softens the film to allow removal from the skin without pulling any hair off. The multilayered design considers soft mechanics in each layer and will offer new insights to improve wound dressing performance and patient comfort.

Phenotyping Alfalfa (Medicago sativa L.) Root Structure Architecture via Integrating Confident Machine Learning with ResNet-18.

Background: Root system architecture (RSA) is of growing interest in implementing plant improvements with belowground root traits. Modern computing technology applied to images offers new pathways forward to plant trait improvements and selection through RSA analysis (using images to discern/classify root types and traits). However, a major stumbling block to image-based RSA phenotyping is image label noise, which reduces the accuracies of models that take images as direct inputs. To address the label noise problem, this study utilized an artificial intelligence model capable of classifying the RSA of alfalfa (Medicago sativa L.) directly from images and coupled it with downstream label improvement methods. Images were compared with different model outputs with manual root classifications, and confident machine learning (CL) and reactive machine learning (RL) methods were tested to minimize the effects of subjective labeling to improve labeling and prediction accuracies. Results: The CL algorithm modestly improved the Random Forest model's overall prediction accuracy of the Minnesota dataset (1%) while larger gains in accuracy were observed with the ResNet-18 model results. The ResNet-18 cross-population prediction accuracy was improved (~8% to 13%) with CL compared to the original/preprocessed datasets. Training and testing data combinations with the highest accuracies (86%) resulted from the CL- and/or RL-corrected datasets for predicting taproot RSAs. Similarly, the highest accuracies achieved for the intermediate RSA class resulted from corrected data combinations. The highest overall accuracy (~75%) using the ResNet-18 model involved CL on a pooled dataset containing images from both sample locations. Conclusions: ResNet-18 DNN prediction accuracies of alfalfa RSA image labels are increased when CL and RL are employed. By increasing the dataset to reduce overfitting while concurrently finding and correcting image label errors, it is demonstrated here that accuracy increases by as much as ~11% to 13% can be achieved with semi-automated, computer-assisted preprocessing and data cleaning (CL/RL).