Search Results (53)

Four-dimensional (4D) flow MRI has shown promise for the assessment of aortic hemodynamics. However, data analysis traditionally requires manual and time-consuming human input at several stages. This limits reproducibility and affects analysis workflows, such that large-cohort 4D flow studies are lacking. Here, a fully automated artificial intelligence (AI) 4D flow analysis pipeline was developed and evaluated in a cohort of over 350 subjects. The 4D flow MRI analysis pipeline integrated a series of previously developed and validated deep learning networks, which replaced traditionally manual processing tasks (background-phase correction, noise masking, velocity anti-aliasing, aorta 3D segmentation). Hemodynamic parameters (global aortic pulse wave velocity (PWV), peak velocity, flow energetics) were automatically quantified. The pipeline was evaluated in a heterogeneous single-center cohort of 379 subjects (age = 43.5 ± 18.6 years, 118 female) who underwent 4D flow MRI of the thoracic aorta (n = 147 healthy controls, n = 147 patients with a bicuspid aortic valve [BAV], n = 10 with mechanical valve prostheses, n = 75 pediatric patients with hereditary aortic disease). Pipeline performance with BAV and control data was evaluated by comparing to manual analysis performed by two human observers. A fully automated 4D flow pipeline analysis was successfully performed in 365 of 379 patients (96%). Pipeline-based quantification of aortic hemodynamics was closely correlated with manual analysis results (peak velocity: r = 1.00, p < 0.001; PWV: r = 0.99, p < 0.001; flow energetics: r = 0.99, p < 0.001; overall r ≥ 0.99, p < 0.001). Bland–Altman analysis showed close agreement for all hemodynamic parameters (bias 1–3%, limits of agreement 6–22%). Notably, limits of agreement between different human observers’ quantifications were moderate (4–20%). In addition, the pipeline 4D flow analysis closely reproduced hemodynamic differences between age-matched adult BAV patients and controls (median peak velocity: 1.74 m/s [automated] or 1.76 m/s [manual] BAV vs. 1.31 [auto.] vs. 1.29 [manu.] controls, p < 0.005; PWV: 6.4–6.6 m/s all groups, any processing [no significant differences]; kinetic energy: 4.9 μJ [auto.] or 5.0 μJ [manu.] BAV vs. 3.1 μJ [both] control, p < 0.005). This study presents a framework for the complete automation of quantitative 4D flow MRI data processing with a failure rate of less than 5%, offering improved measurement reliability in quantitative 4D flow MRI. Future studies are warranted to reduced failure rates and evaluate pipeline performance across multiple centers. Full article

Background: Cytomegalovirus (CMV) infection and age impact immune responses to vaccines. The effect of sex remains controversial. We investigated the relationship between cytomegalovirus-seropositivity, age, and sex and the immunogenicity of the recombinant (RZV) and live (ZVL) zoster vaccines in adults ≥50 years of age. Methods: Varicella zoster virus (VZV) glycoprotein E (gE)-specific antibody, antibody avidity, and cell-mediated immunity (CMI) were measured pre-vaccination and at regular intervals over 5 years post-vaccination in 80 RZV and 79 ZVL recipients, including 91 cytomegalovirus-seropositive and 90 female participants. Results: Differences associated with CMV-seropositivity: lower VZV-gE-CMI in RZV recipients after the first dose of vaccine, but no differences after the 2nd dose; lower VZV-gE-specific antibody avidity in ZVL recipients; and more abundant Th1 and senescent T cells (Tsen) and less abundant regulatory (Treg) and tissue-resident memory T cells (Trm). Differences associated with older age: lower antibody responses in RZV recipients and lower Th1 cells. Differences associated with sex: none for immunogenicity of either vaccine. Differences associated with T cell subset abundance: higher Tsens and lower Tregs or Trms were associated with lower post-dose 1 VZV-gE-specific CMI in RZV recipients, and higher Th1s were associated with higher antibody concentrations. Conclusions: The correlation of CMV- and age-associated T cell subsets with the immunogenicity of ZVLs and RZVs suggests that T cell imprinting contributes to the effect of age and CMV on vaccine responses. Full article

Metaphylaxis or treating the entire population of cattle at arrival with an antimicrobial has been studied extensively in the cattle industry; however, little information is available on the impacts of treating only a proportion of the population with antimicrobials at arrival. The study objective was to determine potential associations between the proportion of animals in a pen treated with antimicrobial therapy with pen performance and nasopharyngeal microbiome. Yearling steers (n = 160) were randomly allocated to study pens (n = 40) and pens were systematically randomized to one of two antimicrobial treatments (META: all four head received tulathromycin; MIXED: two of four head randomly selected to receive tulathromycin). The study was conducted in conjunction with an essential oil feeding trial. Deep nasal pharyngeal (DNP) swabs were collected from every steer at Days 0, 14, 28, and 56. All DNP swabs were individually cultured for Pasteurella multocida and Mannheimia haemolytica. Samples of DNA were extracted from DNP swabs, pooled by pen, and analyzed by metagenomic shotgun sequencing to compare nasopharyngeal microbiome composition and quantity of resistance genes between test groups. Neither antimicrobial nor essential oil treatment groups had any significant associations with performance or DNP microbiome. Sampling day was significantly associated with alpha and beta diversity at the species level. Shannon’s diversity and Inverse Simpson diversity were significantly lower on Day 14 versus both Day 0 and Day 56. These data indicated a shift in microbial populations across study days; however, the microbiome diversity and relative abundance were not significantly different between antimicrobial treatment groups. Full article

Bacteria-related infections remain a leading cause of dental implant failures. Despite the successful history of titanium implants, naturally forming oxides lack antibacterial properties. Crystalline oxides, modified through anodization processes, have shown photocatalytic-induced antibacterial properties when exposed to sufficient energy sources such as UVA light. Chemically doping these oxides with some metallic and non-metallic elements has been shown to enhance their photocatalytic activity (PCA). The present study’s objectives were to assess the relative UVA and violet-light-irradiated PCA levels, bacterial attachment levels, and pre-osteoblast early cell viability levels of phosphorus-doped and phosphorus-and-silver-doped anatase-phase oxides. Each oxide revealed similar surface topographies and surface porosity levels. However, the phosphorus-and-silver-doped oxides exhibited significantly higher PCA levels compared to the phosphorus-doped oxide counterpart after irradiation with 365 nm UVA (p < 0.0001) or 410 nm violet (p = 0.007 and 0.03) light. The phosphorus-doped oxides and phosphorus-and-silver-doped oxides revealed similar Staphylococcus aureus attachment levels after 60 min of UVA irradiation. The phosphorus-and-silver-doped oxides exhibited significantly increased 7-day cell viability compared to their phosphorus-doped oxide counterparts. Thus, it was concluded that the silver doping additions to the oxides show much promise for biomaterials applications and warrant further exploration. Full article

The reduction in the blood supply following the 2019 coronavirus pandemic has been exacerbated by the increased use of balanced resuscitation with blood components including whole blood in urban trauma centers. This reduction of the blood supply has diminished the ability of blood banks to maintain a constant supply to meet the demands associated with periodic surges of urban trauma resuscitation. This scarcity has highlighted the need for increased vigilance through blood product stewardship, particularly among severely bleeding trauma patients (SBTPs). This stewardship can be enhanced by the identification of reliable clinical and laboratory parameters which accurately indicate when massive transfusion is futile. Consequently, there has been a recent attempt to develop scoring systems in the prehospital and emergency department settings which include clinical, laboratory, and physiologic parameters and blood products per hour transfused as predictors of futile resuscitation. Defining futility in SBTPs, however, remains unclear, and there is only nascent literature which defines those criteria which reliably predict futility in SBTPs. The purpose of this review is to provide a focused examination of the literature in order to define reliable parameters of futility in SBTPs. The knowledge of these reliable parameters of futility may help define a foundation for drawing conclusions which will provide a clear roadmap for traumatologists when confronted with SBTPs who are candidates for the declaration of futility. Therefore, we systematically reviewed the literature regarding the definition of futile resuscitation for patients with trauma-induced hemorrhagic shock, and we propose a concise roadmap for clinicians to help them use well-defined clinical, laboratory, and viscoelastic parameters which can define futility. Full article

Zinc is integral to diverse biological functions, acting catalytically, structurally, and supportively in essential enzyme cycles, despite its limited amounts in the body. Targeting zinc enzymes with potent drugs, such as Vorinostat, demonstrates the therapeutic efficacy of zinc-binding ligands, notably in cutaneous T-cell lymphoma treatments. Our study merges experimental and theoretical approaches to analyze the coordination of 8-hydroxylquinoline (8HQ) inhibitors with biomimetic zinc complexes and human histone deacetylase 8 (HDAC8), a monozinc hydrolase enzyme. Assessing 10 8HQ derivatives for structural and electronic characteristics against these models, we observe minimal inhibition efficacy, corroborated through protein–ligand docking analyses, highlighting the complexities of inhibitor–zinc enzyme interactions and suggesting intricate noncovalent interactions that are important for ligand binding to enzymes not accounted for in model zinc hydrolase mimics. Full article

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders. Full article

In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) have replaced endocrine therapy alone as the standard of care; however, several barriers to treatment initiation still exist. We assessed social determinants of health (SDOH) and other factors associated with the initiation of CDK4/6i for HR+/HER2− MBC in the Medicare population. Using a retrospective cohort design, patients aged ≥65 years and diagnosed during 2015–2017 were selected from the SEER-Medicare database. Time from MBC diagnosis to first CDK4/6i initiation was the study outcome. The effect of SDOH measures and other predictors on the outcome was assessed using the multivariable Fine and Gray hazard modeling. Of 752 eligible women, 352 (46.8%) initiated CDK4/6i after MBC diagnosis (median time to initiation: 27.9 months). In adjusted analysis, SDOH factors significantly associated with CDK4/6i initiation included high versus low median household income (HHI) (hazard ratio [HR] = 1.70; 95% CI = 1.03–2.81) and the percentage of population with high versus low Medicare-only coverage (HR = 1.54; 95% CI = 1.04–2.27). In summary, older Medicare patients with HR+/HER2− MBC residing in areas with high median HHI and a high proportion of Medicare-only coverage had higher rates of initiating CDK4/6i, suggesting inequitable access to these novel, effective treatments and a need for policy intervention. Full article

Titanium alloys are commonly used for implants, but the naturally forming oxides are bioinert and not ideal for bacterial resistance or osseointegration. Anodization processes are a modification technique that can crystallize the oxides, alter oxide surface topography, and introduce beneficial chemistries. Crystalline titanium oxides are known to exhibit photocatalytic activity (PCA) under UVA light. Anodization was used to create mixed-phase oxides on six titanium alloys including commercially pure titanium (CPTi), Ti-6Al-4V (TAV), Ti-6Al-7Nb (TAN), two forms of Ti-15Mo (TiMo-β and TiMo-αβ), and Ti-35Nb-7Zr-5Ta (TNZT). Combined EDS and XPS analyses showed uptake of the electrolyte and substrate alloying elements into the oxides. The relative oxide PCA was measured using methylene blue degradation assays. CPTi and TAN oxides exhibited increased PCA compared to other alloys. Combined XRD and EBSD oxide phase analyses revealed an unfavorable arrangement of anatase and rutile phases near the outermost surfaces, which may have reduced PCA for other oxides. The relative Staphylococcus aureus attachment to each oxide was also assessed. The CPTi and TiMo-αβ oxides showed significantly reduced S. aureus attachment after 1 h of UVA compared to un-anodized CPTi. Cell culture results verified that the UVA irradiation did not negatively influence the MC3T3-E1 attachment or proliferation on the mixed-phase oxides. Full article

We describe the process to design, architect, and implement a transformative enhancement of the Event Horizon Telescope (EHT). This program—the next-generation Event Horizon Telescope (ngEHT)—will form a networked global array of radio dishes capable of making high-fidelity real-time movies of supermassive black holes (SMBH) and their emanating jets. This builds upon the EHT principally by deploying additional modest-diameter dishes to optimized geographic locations to enhance the current global mm/submm wavelength Very Long Baseline Interferometric (VLBI) array, which has, to date, utilized mostly pre-existing radio telescopes. The ngEHT program further focuses on observing at three frequencies simultaneously for increased sensitivity and Fourier spatial frequency coverage. Here, the concept, science goals, design considerations, station siting, and instrument prototyping are discussed, and a preliminary reference array to be implemented in phases is described. Full article

The MSL Curiosity rover investigated dark, Mn-P-enriched nodules in shallow lacustrine/fluvial sediments at the Groken site in Glen Torridon, Gale Crater, Mars. Applying all relevant information from the rover, the nodules are interpreted as pseudomorphs after original crystals of vivianite, (Fe²⁺,Mn²⁺)₃(PO₄)₂·8H₂O, that cemented the sediment soon after deposition. The nodules appear to have flat faces and linear boundaries and stand above the surrounding siltstone. ChemCam LIBS (laser-induced breakdown spectrometry) shows that the nodules have MnO abundances approximately twenty times those of the surrounding siltstone matrix, contain little CaO, and have SiO₂ and Al₂O₃ abundances similar to those of the siltstone. A deconvolution of APXS analyses of nodule-bearing targets, interpreted here as representing the nodules’ non-silicate components, shows high concentrations of MnO, P₂O₅, and FeO and a molar ratio P/Mn = 2. Visible to near-infrared reflectance of the nodules (by ChemCam passive and Mastcam multispectral) is dark and relatively flat, consistent with a mixture of host siltstone, hematite, and a dark spectrally bland material (like pyrolusite, MnO₂). A drill sample at the site is shown to contain minimal nodule material, implying that analyses by the CheMin and SAM instruments do not constrain the nodules’ mineralogy or composition. The fact that the nodules contain P and Mn in a small molar integer ratio, P/Mn = 2, suggests that the nodules contained a stoichiometric Mn-phosphate mineral, in which Fe did (i.e., could) not substitute for Mn. The most likely such minerals are laueite and strunzite, Mn²⁺Fe³⁺₂(PO₄)₂(OH)₂·8H₂O and –6H₂O, respectively, which occur on Earth as alteration products of other Mn-bearing phosphates including vivianite. Vivianite is a common primary and diagenetic precipitate from low-oxygen, P-enriched waters. Calculated phase equilibria show Mn-bearing vivianite could be replaced by laueite or strunzite and then by hematite plus pyrolusite as the system became more oxidizing and acidic. These data suggest that the nodules originated as vivianite, forming as euhedral crystals in the sediment, enclosing sediment grains as they grew. After formation, the nodules were oxidized—first to laueite/strunzite yielding the diagnostic P/Mn ratio, and then to hematite plus an undefined Mn oxy-hydroxide (like pyrolusite). The limited occurrence of these Mn-Fe-P nodules, both in space and time (i.e., stratigraphic position), suggests a local control on their origin. By terrestrial analogies, it is possible that the nodules precipitated near a spring or seep of Mn-rich water, generated during alteration of olivine in the underlying sediments. Full article

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS. Full article

In April 2019, the Event Horizon Telescope (EHT) Collaboration successfully imaged a supermassive black hole (SMBH) for the first time, revealing the apparent “shadow” cast by the dark compact object M87${}^{*}$ in the center of the elliptical galaxy Virgo A [...] Full article

Background: Squamous cell carcinoma of the anal canal (SCCA) is rare. Most cases are diagnosed in a localized setting. Metastatic SCCA is rare, and investigation has been limited in the past for these patients. We believe that hepatic-only metastatic disease could have a unique treatment landscape compared to diseases with diffuse metastatic involvement. Here, we describe cases at our institution. Methods: We reviewed eight SCCA cases with hepatic-only metastatic disease (diagnosed February 2018–January 2022). The objectives were to determine the overall survival and disease-free survival with this approach. Results: The median age was 62 years old (yo). Patients had an ECOG of 0–1. All patients received definitive chemoradiation to their primary anal tumor. A median of three months of neoadjuvant systemic therapy was provided. All patients had a response on their first scan after systemic therapy. Sixty-two percent received carboplatin + paclitaxel. A complete pathologic response was seen in 62% of patients. At their last follow-up, all patients were alive. Three patients had recurrent disease. The estimated 1-year disease-free survival probability was 56.2%. Conclusion: Our report shows the feasibility of a curative-intent approach for patients with hepatic-only metastatic SCCA following the neoadjuvant application of carboplatin + paclitaxel. This approach appears promising in these select patients and warrants further investigation. Full article

Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical prostatectomy samples to the Australian Prostate Cancer Bioresource between 2006 and 2014. The prediction of CR was the primary outcome (median time to CR 79.8 months), and BCR was assessed as a secondary outcome (median time to BCR 41.7 months). The associations of (1) H&E ISUP grade groups and (2) modified ISUP grade groups informed by the Appl1, Sortilin and Syndecan-1 immunohistochemistry (IHC) labelling were modelled with BCR and CR using Cox proportional hazard approaches. IHC-assisted grading was more predictive than H&E for BCR (C-statistic 0.63 vs. 0.59) and CR (C-statistic 0.71 vs. 0.66). On adjusted analysis, IHC-assisted ISUP grading was independently associated with both outcome measures. IHC-assisted ISUP grading using the biomarker panel was an independent predictor of individual BCR and CR. Prospective studies are needed to further validate this biomarker technology and to define BCR and CR associations in real-world cohorts. Full article