Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos.

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.

Deciphering human macrophage development at single-cell resolution.

Macrophages are the first cells of the nascent immune system to emerge during embryonic development. In mice, embryonic macrophages infiltrate developing organs, where they differentiate symbiotically into tissue-resident macrophages (TRMs)1. However, our understanding of the origins and specialization of macrophages in human embryos is limited. Here we isolated CD45+ haematopoietic cells from human embryos at Carnegie stages 11 to 23 and subjected them to transcriptomic profiling by single-cell RNA sequencing, followed by functional characterization of a population of CD45+CD34+CD44+ yolk sac-derived myeloid-biased progenitors (YSMPs) by single-cell culture. We also mapped macrophage heterogeneity across multiple anatomical sites and identified diverse subsets, including various types of embryonic TRM (in the head, liver, lung and skin). We further traced the specification trajectories of TRMs from either yolk sac-derived primitive macrophages or YSMP-derived embryonic liver monocytes using both transcriptomic and developmental staging information, with a focus on microglia. Finally, we evaluated the molecular similarities between embryonic TRMs and their adult counterparts. Our data represent a comprehensive characterization of the spatiotemporal dynamics of early macrophage development during human embryogenesis, providing a reference for future studies of the development and function of human TRMs.

YACHT: an ANI-based statistical test to detect microbial presence/absence in a metagenomic sample.

MOTIVATION: In metagenomics, the study of environmentally associated microbial communities from their sampled DNA, one of the most fundamental computational tasks is that of determining which genomes from a reference database are present or absent in a given sample metagenome. Existing tools generally return point estimates, with no associated confidence or uncertainty associated with it. This has led to practitioners experiencing difficulty when interpreting the results from these tools, particularly for low-abundance organisms as these often reside in the "noisy tail" of incorrect predictions. Furthermore, few tools account for the fact that reference databases are often incomplete and rarely, if ever, contain exact replicas of genomes present in an environmentally derived metagenome. RESULTS: We present solutions for these issues by introducing the algorithm YACHT: Yes/No Answers to Community membership via Hypothesis Testing. This approach introduces a statistical framework that accounts for sequence divergence between the reference and sample genomes, in terms of ANI, as well as incomplete sequencing depth, thus providing a hypothesis test for determining the presence or absence of a reference genome in a sample. After introducing our approach, we quantify its statistical power and how this changes with varying parameters. Subsequently, we perform extensive experiments using both simulated and real data to confirm the accuracy and scalability of this approach. AVAILABILITY AND IMPLEMENTATION: The source code implementing this approach is available via Conda and at https://github.com/KoslickiLab/YACHT. We also provide the code for reproducing experiments at https://github.com/KoslickiLab/YACHT-reproducibles.

rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

ARAX: a graph-based modular reasoning tool for translational biomedicine.

MOTIVATION: With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine-supporting that language-that federates semantically integrated knowledge-bases. RESULTS: We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface (API). ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user's query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX's application and utility in specific disease contexts, we present several use-case examples. AVAILABILITY AND IMPLEMENTATION: The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web API endpoint at arax.rtx.ai/api/arax/v1.3/ui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dilute Povidone-Iodine Solution Soaking Is Ineffective in Improving Outcomes of Necrotizing Fasciitis Caused by Diabetic Foot.

ABSTRACT: Wound soaking is a physical debridement method that helps reduce bacterial colonization and consequently promotes wound healing. Although soaking in povidone-iodine solution was ineffective in reducing bacterial colonization in acute trauma wounds, there is still a lack of evidence supporting the efficacy of this method in treating severe soft tissue infection. This study aimed to explore the effects of wound soaking in 1% dilute povidone-iodine solution on necrotizing fasciitis caused by diabetic foot ulcers. We retrospectively reviewed and finally included 153 patients who were admitted because of diabetic foot ulcers after undergoing fasciotomy for necrotizing infection from January 2018 to December 2021. Results showed no statistical difference in the outcomes between patients in the soaking and nonsoaking groups. End-stage renal disease (P = 0.029) and high serum C-reactive protein level (P = 0.007) were the only independent factors for below-knee amputation in the univariate and multivariate logistic regression analyses. Therefore, soaking diabetic wounds with severe infection in 1% dilute povidone-iodine solution may not reduce the hospital length of stay, risk of below-knee amputation, and readmission rate.

Clarifying the mechanism of apigenin against blood-brain barrier disruption in ischemic stroke using systems pharmacology.

Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood-brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients' death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.

Performance evaluation of a deep learning-based cascaded HRNet model for automatic measurement of X-ray imaging parameters of lumbar sagittal curvature.

PURPOSE: To develop a deep learning-based cascaded HRNet model, in order to automatically measure X-ray imaging parameters of lumbar sagittal curvature and to evaluate its prediction performance. METHODS: A total of 3730 lumbar lateral digital radiography (DR) images were collected from picture archiving and communication system (PACS). Among them, 3150 images were randomly selected as the training dataset and validation dataset, and 580 images as the test dataset. The landmarks of the lumbar curve index (LCI), lumbar lordosis angle (LLA), sacral slope (SS), lumbar lordosis index (LLI), and the posterior edge tangent angle of the vertebral body (PTA) were identified and marked. The measured results of landmarks on the test dataset were compared with the mean values of manual measurement as the reference standard. Percentage of correct key-points (PCK), intra-class correlation coefficient (ICC), Pearson correlation coefficient (r), mean absolute error (MAE), mean square error (MSE), root-mean-square error (RMSE), and Bland-Altman plot were used to evaluate the performance of the cascade HRNet model. RESULTS: The PCK of the cascaded HRNet model was 97.9-100% in the 3 mm distance threshold. The mean differences between the reference standard and the predicted values for LCI, LLA, SS, LLI, and PTA were 0.43 mm, 0.99°, 1.11°, 0.01 mm, and 0.23°, respectively. There were strong correlation and consistency of the five parameters between the cascaded HRNet model and manual measurements (ICC = 0.989-0.999, R = 0.991-0.999, MAE = 0.63-1.65, MSE = 0.61-4.06, RMSE = 0.78-2.01). CONCLUSION: The cascaded HRNet model based on deep learning algorithm could accurately identify the sagittal curvature-related landmarks on lateral lumbar DR images and automatically measure the relevant parameters, which is of great significance in clinical application.

Total Surface Area of a Through-and-Through Oromandibular Defect Is Associated With Thromboembolic Events for Reconstruction With a Single Fibula Free Flap.

BACKGROUND: Reconstruction of through-and-through composite oromandibular defects (COMDs) has been a challenge to plastic surgeons for decades. When using a free osteoseptocutaneous fibular flap, the skin paddle is restricted by the orientation of the peroneal vessels and the inset of bone segment(s). Although the combination of double flaps for extensive COMDs is viable and reliable, the decision of single- or double-flap reconstruction is still debated, and the risk factors leading to complications and flap failure of single-flap reconstruction are less discussed. AIM AND OBJECTIVES: The aim of this study was to determine objectively predictive factors for postoperative vascular complications in through-and-through COMDs reconstructed with a single fibula flap. METHODS: This was a retrospective cohort study in patients who underwent single free fibular flap reconstruction for through-and-through COMDs in a tertiary medical center from 2011 to 2020. The enrolled patients' characteristics, surgical methods, thromboembolic event, flap outcomes, intensive care unit care, and total hospital length of stay were analyzed. RESULTS: A total of 43 consecutive patients were included in this study. Patients were categorized into a group without thromboembolic events (n = 35) and a group with thromboembolic events (n = 8). The 8 subjects with thromboembolic events were failed to be salvaged. There was no significant difference in age, body mass index, smoking, hypertension, diabetes mellitus, and history of radiotherapy. The length of bony defect (6.70 ± 1.95 vs 9.04 ± 2.96, P = 0.004) and the total surface area (105.99 ± 60.33 vs 169.38 ± 41.21, P = 0.004) were the 2 factors that showed a significant difference between the groups. Total surface area was the only significant factor in univariate logistic regression for thromboembolic event (P = 0.020; odds ratio, 1.02; 95% confidence interval [CI], 1.003-1.033) and also in multivariate logistic regression analysis after adjusting confounding factors (P = 0.033; odds ratio, 1.026; 95% CI, 1.002-1.051).The cutoff level of total surface area in determining thromboembolic event development was 159 cm2 (P = 0.005; sensitivity of 75% and specificity of 82.9%; 95% CI, 0.684-0.952). CONCLUSIONS: Free fibula flap has its advantages and drawbacks on mandible restoration. Because there is a lack of indicators before, a large total surface area may be an objective reference for single-flap reconstruction of through-and-through COMDs due to an elevated risk of thromboembolic event.

RTX-KG2: a system for building a semantically standardized knowledge graph for translational biomedicine.

BACKGROUND: Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). RESULTS: To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building-and hosting a web API for querying-a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. CONCLUSION: RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .

Regulation of the Assembled Structure of a Flexible Porphyrin Derivative Containing Tetra Isophthalic Acids by Coronene or Different Pyridines.

Based on previous research, a new coassembly formed by a porphyrin derivative (IPETPP), which contains a flexible substituent of m-phthalic acid, is observed with coronene (COR) molecules at a higher concentration. Besides, a fresh IPETPP self-assembly formed at a lower concentration and another new coassembly with COR molecules are obtained. Moreover, the addition of a series of bipyridines alters the diamond arrangement of IPETPP, which enhances the stability of the two-component structures. It is unprecedented that bipyridine derivatives break intermolecular hydrogen bonds containing m-phthalic acid substituents. All the coassemblies are investigated by scanning tunneling microscopy on a highly oriented pyrolytic graphite. Combined with density functional theory, the formation mechanism of the assembled structures is revealed. These results would contribute to understanding the interfacial crystal behaviors and probably provide an efficient pathway to regulate the binary structures.

Accuracy of the Application of 3-Dimensional Printing Models in Orbital Blowout Fractures-A Preliminary Study.

BACKGROUND: Application of 3-dimensional (3D) printing technology has grown in the medical field over the past 2 decades. In managing orbital blowout fractures, 3D printed models can be used as intraoperative navigators and could shorten the operational time by facilitating prebending or shaping of the mesh preoperatively. However, a comparison of the accuracy of computed tomography (CT) images and printed 3D models is lacking. MATERIAL AND METHODS: This is a single-center retrospective study. Patients with unilateral orbital blowout fracture and signed up for customized 3D printing model were included. Reference points for the 2D distance were defined (intersupraorbital notch distance, transverse horizontal, sagittal vertical, and anteroposterior axes for orbital cavity) and measured directly on 3D printing models and on corresponding CT images. The difference and correlation analysis were conducted. RESULTS: In total, 9 patients were reviewed from June 2017 to December 2020. The mean difference in the intersupraorbital notch measurement between the 2 modules was -0.14 mm (P = 0.67). The mean difference in the distance measured from the modules in the horizontal, vertical, and anteroposterior axes of the traumatic orbits was 0.06 mm (P = 0.85), -0.23 mm (P = 0.47), and 0.51 mm (P = 0.32), whereas that of the unaffected orbits was 0.16 mm (P = 0.44), 0.34 mm (P = 0.24), and 0.1 mm (P = 0.88), respectively. Although 2D parameter differences (<1 mm) between 3D printing models and CT images were discovered, they were not statistically significant. CONCLUSIONS: Three-dimensional printing models showed high identity and correlation to CT image. Therefore, personalized models might be a reliable tool of virtual surgery or as a guide in realistic surgical scenarios for orbital blowout fractures.

Rational Design of Meso-Phosphino-Substituted BODIPY Probes for Imaging Hypochlorite in Living Cells and Mice.

Meso-phosphino-substituted BODIPY probes were developed for concise and rapid detection of hypochlorite (ClO-). Interestingly, the probe BP gave a turn-on fluorescence response by shutting the photoinduced electron transfer (PET) effect and extending the coplanar conjugated π-system. In contrast, the probe TMBP showed a colorimetric response toward ClO-. The key role of the steric repulsions was revealed to be for altering the electronic distribution of the BODIPY core, resulting in these obviously different responses. Finally, the probe BP, with high selectivity and sensitivity toward ClO- (LOD = 1.9 nM; response time, <15 s), was further employed in imaging the variations of exogenous and endogenous hypochlorite (ClO-) in living RAW 264.7 cells and mouse inflammation models. If wisely utilized, this strategy with meso-phosphino BODIPY dyes may serve as a powerful platform for the preparation of novel chemosensors.

Progress in self-assemblies of macrocycles at the liquid/solid interface.

Macrocyclic self-assemblies have gained great interest for diversified structures and potential applications, such as catalysis, magnetism, photovoltaic devices, organic light-emitting diodes. Macrocycles can present regular assembly systems at the liquid/solid interface due to theπ-conjugated structures. Furthermore, suitable guest molecules can be selected for constructing multi-component supramolecular co-assemblies. This review mainly summarizes macrocyclic self-assembly structures with different shapes in recent years. All of the studies are completed with the assistance of scanning tunneling microscope at the liquid/solid interface.

Asiatic acid inhibits angiogenesis and vascular permeability through the VEGF/VEGFR2 signaling pathway to inhibit the growth and metastasis of breast cancer in mice.

Anti-angiogenic medicines have been evaluated as anticancer therapies, however, their use remains limited in clinical practice due to associated adverse effects. Asiatic acid (AA) is known to have broad-spectrum anticancer properties, however, its effects on angiogenesis in breast cancer remain to be fully established. In this study, we analyzed the inhibitory effects of AA on angiogenesis using human umbilical vein endothelial cells (HUVECs) cultured in vitro and on the growth and metastasis of a subcutaneous breast cancer 4T1 tumor model and a lung metastasis model in vivo. AA significantly inhibited HUVECs proliferation, migration, and tube formation in vitro. In vivo, AA significantly reduced the microvascular density and blood vascular permeability in breast cancer tumors and inhibited growth and lung metastasis. AA inhibited the expression of vascular endothelial growth factor (VEGF) in HUVECs and subsequently downregulated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream target proteins including ERK1/2, Src, and FAK. These results indicate that AA significantly inhibits angiogenesis and blood vessel permeability through the VEGF/VEGFR2 signal axis to inhibit the growth and metastasis of breast cancer. Our data strongly demonstrate the potential applications of AA in the treatment of breast cancer.

Reference Standardization for Quantification and Harmonization of Large-Scale Metabolomics.

Reference standardization was developed to address quantification and harmonization challenges for high-resolution metabolomics (HRM) data collected across different studies or analytical methods. Reference standardization relies on the concurrent analysis of calibrated pooled reference samples at predefined intervals and enables a single-step batch correction and quantification for high-throughput metabolomics. Here, we provide quantitative measures of approximately 200 metabolites for each of three pooled reference materials (220 metabolites for Qstd3, 211 metabolites for CHEAR, 204 metabolites for NIST1950) and show application of this approach for quantification supports harmonization of metabolomics data collected from 3677 human samples in 17 separate studies analyzed by two complementary HRM methods over a 17-month period. The results establish reference standardization as a method suitable for harmonizing large-scale metabolomics data and extending capabilities to quantify large numbers of known and unidentified metabolites detected by high-resolution mass spectrometry methods.

A Novel Broadband Monopole Antenna with T-Slot, CB-CPW, Parasitic Stripe and Heart-Shaped Slice for 5G Applications.

This paper presents a novel broadband monopole antenna that was equipped with a bottom semicircle ground structure, a parasitic patch, a T-shaped slot, s transmission line, a parasitic strip, heart-shaped slices and a coplanar waveguide (CPW). The simulation results revealed that the proposed design had a relatively high return loss, a wide bandwidth and high efficiency. A prototype of the proposed antenna with an overall size of 0.94 λ0 × 0.94 λ0 × 0.02 λ0 (λ0 is the free-space wavelength) was fabricated and measured. The measurement results showed that the prototype had a bandwidth of 4.02 GHz (4.69-8.71 GHz) and a relative bandwidth of 60%. Besides, the maximum gain was 3.31 dBi and the maximum efficiency was 91.1% in the range of 5 to 8.5 GHz. Furthermore, it was found that the prototype almost achieved omnidirectional radiation. Its operating frequency band covered those of industrial scientific medical (ISM) (5.725-5.850 GHz), the radio frequency identification (RFID) (5.8 GHz) and the wireless local area network (WLAN) (5.15-5.25 GHz and 5.725-5.825 GHz).

xMWAS: a data-driven integration and differential network analysis tool.

Summary: Integrative omics is a central component of most systems biology studies. Computational methods are required for extracting meaningful relationships across different omics layers. Various tools have been developed to facilitate integration of paired heterogenous omics data; however most existing tools allow integration of only two omics datasets. Furthermore, existing data integration tools do not incorporate additional steps of identifying sub-networks or communities of highly connected entities and evaluating the topology of the integrative network under different conditions. Here we present xMWAS, a software for data integration, network visualization, clustering, and differential network analysis of data from biochemical and phenotypic assays, and two or more omics platforms. Availability and implementation: https://kuppal.shinyapps.io/xmwas (Online) and https://github.com/kuppal2/xMWAS/ (R). Contact: kuppal2@emory.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Metabolomics of Aerobic Exercise in Chronic Stroke Survivors: A Pilot Study.

BACKGROUND: Understanding the metabolic response to exercise may aid in optimizing stroke management. Therefore, the purpose of this pilot study was to evaluate plasma metabolomic profiles in chronic stroke survivors following aerobic exercise training. METHODS: Participants (age: 62 ± 1 years, body mass index: 31 ± 1 kg/m2, mean ± standard error of the mean) were randomized to 6 months of treadmill exercise (N = 17) or whole-body stretching (N = 8) with preintervention and postintervention measurement of aerobic capacity (VO2peak). Linear models for microarray data expression analysis was performed to determine metabolic changes over time, and Mummichog was used for pathway enrichment analysis following analysis of plasma samples by high-performance liquid chromatography coupled to ultrahigh resolution mass spectrometry. RESULTS: VO2peak change was greater following exercise than stretching (18.9% versus -.2%; P < .01). Pathway enrichment analysis of differentially expressed metabolites results showed significant enrichment in 4 pathways following treadmill exercise, 3 of which (heparan-, chondroitin-, keratan-sulfate degradation) involved connective tissue metabolism and the fourth involve lipid signaling (linoleate metabolism). More pathways were altered in pre and post comparisons of stretching, including branched-chain amino acid, tryptophan, tyrosine, and urea cycle, which could indicate loss of lean body mass. CONCLUSIONS: These preliminary data show different metabolic changes due to treadmill training and stretching in chronic stroke survivors and suggest that in addition to improved aerobic capacity, weight-bearing activity, like walking, could protect against loss of lean body mass. Future studies are needed to examine the relationship between changes in metabolomic profiles to reductions in cardiometabolic risk after treadmill rehabilitation.

Driving cessation over a 24-year period: Dementia severity and cerebrospinal fluid biomarkers.

INTRODUCTION: With 36 million older adult U.S. drivers, safety is a critical concern, particularly among those with dementia. It is unclear at what stage of Alzheimer's disease (AD) older adults stop driving and whether preclinical AD affects driving cessation. METHODS: Time to driving cessation was examined based on Clinical Dementia Rating (CDR) and AD cerebrospinal fluid biomarkers. 1795 older adults followed up to 24 years received CDR ratings. A subset (591) had cerebrospinal fluid biomarker measurements and was followed up to 17 years. Differences in CDR and biomarker groups as predictors of time to driving cessation were analyzed using Kaplan-Meier curves and Cox proportional models. RESULTS: Higher CDR scores and more abnormal biomarker measurements predicted a shorter time to driving cessation. DISCUSSION: Higher levels of AD biomarkers, including among individuals with preclinical AD, lead to earlier driving cessation. Negative functional outcomes of preclinical AD show a nonbenign phase of the disease.