The University of Texas System

Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug–protein–disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346–0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.

Introduction The Leuven Consensus provides a classification scheme for the diagnosis of pharyngeal and upper esophageal sphincter (UES) motor disorders using metrics derived from pharyngeal high‐resolution manometry‐impedance (P‐HRM‐I). Methods Twenty‐six experts with broad multidisciplinary backgrounds contributed their knowledge and experience to this initiative via a formal deliberative Delphi process. Guidance on a swallow assessment protocol as well as diagnostic criteria for UES dysfunction and pharyngeal contractile dysfunction is provided. Results For UES dysfunction, the stepwise evaluation of UES and intrabolus pressure metrics under increasing bolus volume and/or viscosity conditions is used to confirm failure of manometric relaxation and opening of the UES region. For pharyngeal contractile dysfunction, the evaluation of contractile metrics is used to define pharyngeal hypocontractility or hypercontractility. Conclusion These recommendations complement routine instrumental investigations and provide a standardized process, criteria, and nomenclature for P‐HRM‐I assessment of patients reporting symptoms of oropharyngeal dysphagia.

Models of planetary core formation traditionally involve the fractionation of Fe,Ni-metal melts from silicate mantles after extensive silicate melting. However, in planetary bodies that form farther from their central star, where moderately volatile elements are more abundant, high concentrations of oxygen and sulfur stabilize Fe,Ni-sulfides over metals. Here we show that percolative sulfide melt migration can occur in primitive, oxidized mineral assemblages prior to silicate melting in partial melting experiments with meteorites. Complementary experiments with partially molten synthetic sulfides show that fractionation of liquid sulfide from solid residues yields distinct noble metal (Os, Ru, Ir, Pd, and Pt) trace element proportions that match those manifested in the most oxidized meteoritic residues, the brachinites, as well as their complementary basaltic silicate melts. Our experiments provide robust evidence for percolative sulfide melt fractionation in meteorites and indicate that sulfide-dominated cores would be expected in oxidized planetary bodies, including Mars.

The Cambrian edrioasteroid “Totiglobus” spencensis Wen et al., 2019 is redescribed on the basis of a new and exquisitely preserved specimen from the Cambrian Wuliuan of the Spence Shale Member, Langston Formation (Utah). This new occurrence is associated with soft-body preservation of several invertebrate groups and other shelly fossils. The description of “T.” spencensis was originally based on a single poorly preserved specimen. As a result, some of its features, such as curvature of the ambulacra and morphology of floor and cover plates, were misinterpreted or unavailable. The new material allows a new placement in Sprinkleoglobus spencensis n. comb. (Wen et al., 2019) on the basis of the general shape of the theca, attachment disc, and biserial flooring plates with podial pores and multiple cover plate series. The attachment disc of the new specimen lies in contact with a trilobite librigena, supporting evidence that this taxon is one of the earliest known examples of attachment to hard, mineralized substrata among Edrioasteroidea.

Within the context of linear elasticity, approximate analytical solutions are developed for the energy release rate for axisymmetric planar cracks in elastic thin layers sandwiched between two rigid plates. These solutions are validated by comparing them with finite element solutions, and they are applicable to cracks in constrained thin layers made of compressible, nearly incompressible, or incompressible materials. These analytical solutions provide insights into the effects of geometry and material compressibility on fracture of thin layers. In particular, stability of crack growth is discussed under both displacement and force-controlled loading conditions, summarized in stability maps. Remarkably, it is found that, under force-controlled conditions, stable crack growth is possible in incompressible or nearly incompressible layers, but not in compressible layers. We compare the energy release rates for embedded and interfacial cracks, showing that they differ when the cracks are small but become approximately equal for large cracks. The analytical approach is further extended to non-axisymmetric planar cracks in compressible thin layers. However, a similar extension does not apply for cracks in incompressible or nearly incompressible layers.

We perform analytical and quantitative analyses of the motion of a non-integrable pendulum with two degrees of freedom, in which an integrable nonlinear pendulum and a harmonic oscillator are weakly coupled through a non-integrable perturbative interaction, based on the eigenvalue problem of the Liouvillian, which is the generator of time evolution in classical mechanics. The eigenfunctions belonging to the zero eigenvalue of the Liouvillian correspond to the invariants of the motion. The zero eigenvalue of the integrable unperturbed Liouvillian is infinitely degenerate at the resonance point. By applying a perturbation, level repulsion occurs between the eigenstates of the unperturbed system, and some of the degeneracy is lifted, resulting in a non-zero eigenvalue. In order to evaluate the frequency gap caused by the level repulsion, we introduce an auxiliary operator called the collision operator, which is well known in non-equilibrium statistical mechanics. We show that the dependence of the magnitude of a frequency gap on the coupling constant can be quantitatively evaluated by simply finding the condition for the existence of the collision operator, without directly solving the eigenvalue problem.

Background and objectives: Sex steroid hormones have been demonstrated to affect the immune system in multiple sclerosis (MS), and puberty may trigger MS activity. We aimed to evaluate the association between menarche and disease course in pediatric MS through comparison of relapse rates across premenarche, perimenarche, and postmenarche periods. Methods: This is a retrospective analysis of a prospectively followed female cohort with pediatric-onset MS in the US Network of Pediatric MS Centers database. Perimenarche was considered the period from 1 year before to 1 year after the estimated menarche date based on menarche integer age. Relapses were collected prospectively. Negative binomial and repeated-measures Cox regression models were used to assess the association of pubertal development stage with relapse rate, adjusted for race, body mass index, and disease-modifying therapy (DMT). Results: Of 736 participants (all female; mean onset age 14.4 ± 2.8 years; mean menarche age 11.6 ± 1.4 years), onset was in premenarche in 73, perimenarche in 112 (± 1 year of menarche), and postmenarche in 551. The median time of MS onset was 2.8 years after menarche. Most (86%) were exposed to DMT in follow-up. In adjusted negative binomial analysis, the annualized relapse rate during premenarche was 0.43, perimenarche was 0.65, and postmenarche was 0.43 (premenarche rate ratio [RR] 1.00 (95% CI 0.70-1.43) and perimenarche RR 1.52 (95% CI 1.16-1.99), compared with reference of postmenarche, p = 0.0049. In adjusted repeated-events Cox regression analysis, there was increased hazard to relapse in perimenarche and postmenarche compared with premenarche (perimenarche hazard ratio [HR] 1.78 [95% CI 1.17-2.70] and postmenarche HR 1.67 [95% CI 1.12-2.50], compared with reference of premenarche, p = 0.025). In this analysis, use of oral and infusion DMTs significantly lowered the relapse hazard compared with periods of no DMT use (injectable HR 0.98 [95% CI 0.83-1.15], oral HR 0.48 [95% CI 0.37-0.61], and infusion HR 0.24 [95% CI 0.18-0.31], compared with no DMT, p < 0.001). Discussion: Onset of puberty may be a time of increase in disease activity and may require consideration of a change in therapeutic approach. Menarche age was used as a surrogate for puberty, and future studies measuring sex steroid hormones may be informative.

Quantitative photoacoustic computed tomography (qPACT) is an emerging medical imaging modality that carries the promise of high-contrast, fine-resolution imaging of clinically relevant quantities like hemoglobin concentration and blood-oxygen saturation. However, qPACT image reconstruction is governed by a multiphysics, partial differential equation (PDE) based inverse problem that is highly non-linear and severely ill-posed. Compounding the difficulty of the problem is the lack of established design standards for qPACT imaging systems, as there is currently a proliferation of qPACT system designs for various applications and it is unknown which ones are optimal or how to best modify the systems under various design constraints. This work introduces a novel computational approach for the optimal experimental design of qPACT imaging systems based on the Bayesian Cramér–Rao bound (CRB). Our approach incorporates several techniques to address challenges associated with forming the bound in the infinite-dimensional function space setting of qPACT, including priors with trace-class covariance operators and the use of the variational adjoint method to compute derivatives of the log-likelihood function needed in the bound computation. The resulting Bayesian CRB based design metric is computationally efficient and independent of the choice of estimator used to solve the inverse problem. The efficacy of the bound in guiding experimental design was demonstrated in a numerical study of qPACT design schemes under a stylized two-dimensional imaging geometry. To the best of our knowledge, this is the first work to propose Bayesian CRB based design for systems governed by PDEs.

The Early–Middle Jurassic Nazas continental rift province in Mexico has been debated as either anextensional continental arc due to eastward subduction beneath North America or an intracontinentalrift linked to Pangea break-up. New petrographic and U-Pb geochronological data from the La BocaFormation near Ciudad Victoria – a key locality within this province – reveal diverse clastic sources,forming three provenance groups. Group 1 (Juan Capitán Member) crops out in the Huizachal Valleyand consists of volcaniclastic fluvial deposits derived from a local volcanic centre. Group 2 (Agua de LasMinas Member), also found in the Huizachal Valley, overlies Group 1 and has mixed provenance fromlocal volcanic and surrounding basement uplift sources. Both groups transition laterally to deposits ofGroup 3 (San Pedro Member) to the north, which consists of metamorphiclastic fluvial deposits fromthe eastern basement uplift and is not influenced by the volcanic centre. The rapid dilution of volcanicdetritus within ~35 km highlights the limited extent of the volcanic centre as a source of sediment. Ourresults suggest that the Nazas province was more likely formed in a continental rift basin with sparsevolcanic activity linked to Pangea break-up rather than as an extensive volcanic arc.

INTRODUCTION Interventions to treat speech‐language difficulties in primary progressive aphasia (PPA) often use word accuracy as a highly comparable outcome. However, there are more constructs of importance to people with PPA that have received less attention. METHODS Following Core Outcome Set Standards for Development Recommendations (COSSTAD), this study comprised: Stage 1 – systematic review to identify measures; Stage 2 – consensus groups to identify important outcome constructs for people with PPA (n = 82) and care partners (n = 91); Stage 3 – e‐Delphi consensus with 57 researchers. RESULTS The systematic review identified 84 Outcome Measurement Instruments. Core outcome constructs identified included: (1) Participate in conversations with family and friends, (2) get words out, (3) be more fluent, (4) convey a message by any means, and (5) understand what others are saying. Researchers were unable to reach a consensus on measurement instruments. DISCUSSION Further work is required to develop appropriate measurement instruments that address all core outcome constructs important to key stakeholders. Highlights We introduce new symptom‐led perspectives on primary progressive aphasia (PPA). The focus is on non‐fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non‐verbal features of PPA and clinical trajectories is featured. We introduce a symptom‐led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Retrospective analysis. This study sought to report the long-term outcomes of patients that underwent minimally invasive surgery (MIS) correction for Adolescent Idiopathic Scoliosis (AIS) in terms of radiographic, clinical, and patient-reported outcomes. Furthermore, we examined the learning curve of MIS technique over the course of 13 years. Both MIS and open techniques are used to surgically address AIS. MIS techniques are purported to preserve the midline spinal musculature and to decrease estimated blood loss (EBL) and hospital length of stay (LOS). Data were collected at a single tertiary care center of all consecutive AIS patients undergoing deformity surgery from January 2008 to October 2021. Demographic, clinical, and radiographic data were collected at various intervals. Descriptive and inferential analyses were conducted. 70 AIS patients were included in the study. Mean patient age was 16.2 years of which 95.7% were female, with a mean BMI of 21.7. The majority of the patients were Lenke type 1A (60%) followed by Lenke 1B (18.6%) with mean preop Cobb angle as 52.2°. The mean follow-up was approximately 6 years with 35.7% of our cohort meeting the long-term follow-up landmark (> 5 years, 2-11). The mean number of spinal levels treated was 9.3 with mean ASA score of 1.7. Overall, mean EBL was 151 cc with mean OR of 308 min. The mean LOS was 3.94 days with postop Day 1 as the initiation of ambulation. Overall, the percent correction at the last visit was significantly greater than preop (Cobb: 77.6%, p < 0.05). Mean loss of correction on follow-ups was less than 5º. The overall revision rate was 2.9%. At 2 years postop, 98.6% (69/70) of the patients achieved fusion with 100% (24/24) at 5 years, and 96% (24/25) beyond the 5-year mark. Surgeon’s technical proficiency in performing MIS for the treatment of AIS corrections was achieved after 23 cases. Based on our cohort’s 2-11 year follow-up data, we conclude that MIS provides an effective treatment option for AIS reconstruction. Our study indicates that MIS can achieve adequate deformity correction and positive long-term clinical outcomes as indicated by Cobb angle, VAS, ODI, and SRS-22r scores during follow-ups. If the individual goals of AIS surgery can be achieved, consideration should be given to less-invasive techniques. IV.

Background Appendiceal cancer’s mucinous nature and scant cellularity significantly restrict traditional molecular analyses. Single cell sequencing overcomes technical challenges of bulk sequencing but lacks spatial information. To address this, we employed digital spatial profiling to select regions of interest exclusive of mucin pools to better isolate the tumor compartment. Specimens from patients in a recently completed trial of combination immune checkpoint blockade (ICB) and VEGF inhibition (Atezolizumab-Bevacizumab) in metastatic appendiceal cancer¹ were utilized. This was the first trial of ICB in appendix cancer and demonstrated efficacy in this rare malignancy. This offers a mechanism to deconvolute the microenvironment of appendiceal tumors while uncovering biomarkers of response to ICB. Methods Spatial whole transcriptome sequencing was performed on FFPE tissue sections from two moderately-differentiated and two well-differentiated metastatic appendiceal cancers from patients on trial (NCT03074513)¹ using nanoString’s GeoMX Digital Spatial Profiling Platform. Sequential slides were stained with either H&E or fluorescent markers for DNA (SYTO 13), epithelium (PanCK), bacteria (16s) and immune cells (CD45). In collaboration with an appendiceal expert gastrointestinal pathologist, 95 representative regions including tumor, normal epithelium, stroma and immune aggregates were selected. Unsupervised dimension reduction was performed using Uniform Manifold Approximation and Projection (UMAP). Results From 95 regions collected, 76 passed quality control focused on filtering regions with low sequencing reads (<1000), nuclei count (<10) and gene detection rate (<400 genes). Overall, we detected ~14,000 genes above the limit of quantification. Survey of the tumor microenvironment identified small tumor islands (10-200 cells) within expansive pools of mucin (figure 1). We analyzed 6 tumor islands with only one specimen demonstrating bacterial co-localization with tumor. UMAP analysis differentiated transcriptionally distinct normal appendix and adenocarcinoma populations (figure 2). Furthermore, immune aggregates potentially representing two molecularly distinct subtypes of Tertiary Lymphoid Structures (TLSs) were noted in the peri-tumoral vicinity, with TLS1 containing more plasma cells (p=0.015) and a trend towards higher M2 macrophages (p=0.060). TLS2 aggregates demonstrated higher clonality (Gini coefficient p<0.001) and lower diversity (Shannon H p<0.001) (figure 3). Conclusions We successfully identified transcriptionally distinct populations of cells in adenocarcinoma vs. normal tissue and uncovered two potential TLS subtypes in the peri-tumoral landscape. This work represents a significant advancement in studying these rare tumors. Additional specimens from trial participants are undergoing analysis to expand this pilot study. By profiling the landscape of the tumor and peri-tumoral tissue immune microenvironment and correlating with clinical outcomes, we hope to identify biomarkers of therapeutic response. Trial Registration NCT03074513 Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors. Reference • Hornstein NJ, Zeineddine MA, Gunes BB, Pellatt AJ, Knafl M, Zhu H, Willett AF, Yousef A, Liu S, Sun R, Futreal A, Woodman SE, Taggart MW, Overman MJ, Halperin DM, Raghav KP, Shen JP. Efficacy and safety of atezolizumab and bevacizumab in appendiceal adenocarcinoma. Cancer Res Commun 2024 May 29; 4 (5):1363-1368. doi: 10.1158/2767-9764.CRC-24-0019. PMID: 38709066; PMCID: PMC11135244. Ethics Approval This study was conducted under a protocol approved by the University of Texas M.D. Anderson Cancer Center‘s Institutional Review Board. Specific IRB identifier has been withheld due to Institutional Policy on cybersecurity. • Download figure • Open in new tab • Download powerpoint Abstract 90 Figure 1 Appendix cancer spatial transcriptomics. Appendix adenocarcinoma operative specimen spatial transcriptomics reveal tumor islands in mucin pools with adjacent immune aggregates • Download figure • Open in new tab • Download powerpoint Abstract 90 Figure 2 UMAP analysis demonstrates distinct populations of normal appendix and adenocarcinoma tissue • Download figure • Open in new tab • Download powerpoint Abstract 90 Figure 3 Immune cell deconvolution. Immune cell deconvolution of peri-tumoral aggregates suggests two subtypes of Tertiary Lymphoid Structures (TLSs) in appendix cancer specimens

Modeling subsurface controlled-source electromagnetic (CSEM) responses using the finite-element (FE) method is challenging in the presence of highly conductive wellbore casing. The very large conductivity contrast between the casing and the host formation leads to increased computation time and potentially unstable solutions. We address this difficulty by preconditioning an FE solver with an integral equation (IE) primary solution that captures the CSEM response of a realistic-sized steel wellbore casing. Our hybrid IE-FE approach determines the primary field using 2D integral-equation forward modeling and then interpolates the IE-computed solution onto the nodes. Then using an existing FE simulator, we solve for the secondary electric and magnetic fields. This approach removes the need for an ultra-fine FE mesh around the wellbore, thereby improving FE solution stability while greatly reducing FE computation time. Our method is illustrated by modeling the CSEM responses of idealized fluid-bearing zones.

This article introduces an innovative method for optimizing smart manufacturing system (SMS) by combining digital twin technology (DTT) with teaching–learning-based optimization (TBLO). It creates a simulated model of the physical manufacturing environment, enabling real-time monitoring, simulation and analysis. By leveraging the TLBO algorithm, the system enhances the decision-making process for complex manufacturing tasks, facilitating continuous improvement and adaptation to dynamic production demands. The proposed framework aims to minimize production costs, reduce downtime and improve overall efficiency by optimizing key parameters such as resource allocation, production scheduling and machine performance. Experimental results demonstrate that the DT-TLBO approach can reduce production costs by up to 20%, decrease downtime by 30% and improve overall system efficiency by 25%. This innovative combination of advanced technologies offers a promising solution for modern manufacturing challenges, paving the way for smarter, more responsive production environments.

Objectives Long-standing atrial fibrillation (AF) may lead to tricuspid regurgitation (TR) and right ventricular dysfunction. However, the effect of acute AF on tricuspid annular (TA) dynamics and three-dimensional geometry is unknown. Methods In eight adult sheep, sonomicrometry crystals were implanted around the tricuspid annulus and right ventricular free wall. Pressure transducers were placed in the right ventricle, left ventricle, and right atrium. After weaning from cardiopulmonary bypass and a period of hemodynamic stabilization, simultaneous sonomicrometry and hemodynamic data were collected in sinus rhythm (SR) and during experimental AF (400b/min right atrial pacing). Annular area, perimeter, dimensions, height, global and regional annular contraction, and strain were calculated based on cubic spline fits to crystal 3D locations. Results Maximal TA area increased from 1084.9±273.9mm² in SR to 1207.5±322.1mm² during AF (p = 0.002). Anteroposterior diameter increased from 36.5±5.0mm to 38.4±5.5mm (p = 0.05). TA contraction decreased from 7±2% in SR to 2±1% in AF (p = 0.001). Anterior, posterior, and septal regional annular contraction decreased from 10±4%, 8±3% and 6±2% to 4±2%, 3±1% and 2±1% for SR and AF, respectively (p<0.05). AF perturbed systolic global annular strain (from -6.52±1.74% to -2.78±1.79%; p = 0.003) and caused annular stretch. Annular height marginally decreased with AF from 5.8±1.9mm to 5.7±2.0mm; p = 0.039. Conclusions Acute experimental AF in healthy sheep was associated with TA dilation, flattening, and decreased total and regional annular contractility. These data may help elucidate the pathophysiology of functional TR associated with AF.