Showing papers by "Michael I. Miller published in 2023"

BrainLine: An Open Pipeline for Connectivity Analysis of Heterogeneous Whole-Brain Fluorescence Volumes

Abstract: Whole-brain fluorescence images require several stages of computational processing to fully reveal the neuron morphology and connectivity information they contain. However, these computational tools are rarely part of an integrated pipeline. Here we present BrainLine, an open-source pipeline that interfaces with existing software to provide registration, axon segmentation, soma detection, visualization and analysis of results. By implementing a feedback based training paradigm with BrainLine, we were able to use a single learning algorithm to accurately process a diverse set of whole-brain images generated by light-sheet microscopy. BrainLine is available as part of our Python package brainlit: http://brainlit.neurodata.io/.

Pegozafermin for the Treatment of Severe Hypertriglyceridemia: A Randomized, Double-blind, Placebo-controlled Phase 2 Study (ENTRIGUE STUDY)

Abstract: Purpose: Pegozafermin (PGZ) is a long-acting glycopegylated recombinant analog of human fibroblast growth factor 21 (FGF21) being developed for severe hypertriglyceridemia (SHTG) and non-alcoholic steatohepatitis (NASH). This study evaluates the efficacy, safety, and tolerability of PGZ in subjects with SHTG.

The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial

Abstract: Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl-1 and ≤2,000 mg dl-1). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo -43.7%, 95% confidence interval (CI): -57.1%, -30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (-10.5% and -18.3% for pooled doses compared to 1.1% and -0.6% for placebo (95% CI: -21.5%, -2.0%; P = 0.019 and 95% CI: -30.7%, -5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; -42.2% pooled pegozafermin, -8.3% placebo; 95% CI: -60.9%, -8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).

Examining the intersection of cognitive and physical function measures: Results from the brain networks and mobility (B-NET) study

Abstract: Background and objectives Although evidence exists that measures of mobility and cognition are correlated, it is not known to what extent they overlap, especially across various domains. This study aimed to investigate the intersection of 18 different objective cognitive and physical function measures from a sample of unimpaired adults aged 70 years and older. Research design and methods Canonical correlation analysis was utilized to explore the joint cross-sectional relationship between 13 cognitive and 6 physical function measures in the baseline visit of the Brain Networks and Mobility Function (B-NET) Study (n = 192). Results Mean age of participants was 76.4 years. Two synthetic functions were identified. Function 1 explained 26.3% of the shared variability between the cognition and physical function variables, whereas Function 2 explained 19.5%. Function 1 termed “cognitive and physical speed” related the expanded Short Physical Performance Battery (eSPPB), 400-m walk speed, and Dual Task gait speed measures of physical function to semantic fluency animals scores, Digit Symbol Coding (DSC), and Trail Making Test B. Function 2 termed “complex motor tasks and cognitive tasks” related the Force Plate Postural Sway Foam Task and Dual Task to the following cognitive variables: MoCA Adjusted Score, Verbal Fluency L words, Craft story immediate and delayed recall, and Trail Making Test B. Discussion and implications We identified groups of cognitive and physical functional abilities that were linked in cross-sectional analyses, which may suggest shared underlying neural network pathway(s) related to speed (Function 1) or complexity (Function 2). Translational significance Whether such neural processes decline before measurable functional losses or may be important targets for future interventions that aim to prevent disability also remains to be determined.

Dominique Kalifa. The Belle Époque: A Cultural History, Paris and Beyond. Translated by Susan Emanuel.

Abstract: Journal Article Dominique Kalifa. The Belle Époque: A Cultural History, Paris and Beyond. Translated by Susan Emanuel. Get access Dominique Kalifa. The Belle Époque: A Cultural History, Paris and Beyond. Translated by Susan Emanuel. New York: Columbia University Press, 2021. Pp. 252. Paper $30.00. Michael Miller Michael Miller University of Miami, US Email: mbmiller@miami.edu Search for other works by this author on: Oxford Academic Google Scholar The American Historical Review, Volume 128, Issue 2, June 2023, Pages 1026–1027, https://doi.org/10.1093/ahr/rhad148 Published: 22 June 2023

Microbiome Engineering Using Probiotic Yeast: Saccharomyces boulardii and the Secreted Human Lysozyme Lead to Changes in the Gut Microbiome and Metabolome of Mice

Abstract: Our study identified changes in the microbiome by administering wild-type S. boulardii in mice to healthy mice based on long-read sequencing and demonstrated that a recombinant protein secreted by engineered S. boulardii in the intestine could change the microbiome. Our results provide valuable information for the development of therapeutics using engineered S. boulardii that changes the gut microbiome and host physiology. ABSTRACT The probiotic yeast Saccharomyces boulardii has great potential for use as a chassis for microbiome engineering because of its high resistance to environmental stress, well-developed genetic tools, and the ability to secrete recombinant proteins in the intestine. As oral feeding of lysozyme has been reported to change the gut microbiome and fecal metabolites, we engineered S. boulardii to secrete human lysozyme, and investigated the changes in the microbiome and fecal metabolites in response to the administration of the engineered probiotic yeast into mice. Administration of S. boulardii changed the structure of the gut microbiome by promoting the growth of clostridia and increasing the diversity of strains. The human lysozyme secreted by S. boulardii in the intestine resulted in a unique gut microbiome structure through selective growth. In addition, the administration of probiotic yeast S. boulardii affected host energy metabolism and decreased blood urea and fructose levels, suggesting a mechanism of health benefits in mice. IMPORTANCE Our study identified changes in the microbiome by administering wild-type S. boulardii in mice to healthy mice based on long-read sequencing and demonstrated that a recombinant protein secreted by engineered S. boulardii in the intestine could change the microbiome. Our results provide valuable information for the development of therapeutics using engineered S. boulardii that changes the gut microbiome and host physiology.

Cardiovascular Benefits of Icosapent Ethyl in Patients With and Without Atrial Fibrillation in REDUCE-IT.

Abstract: Background In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), icosapent ethyl (IPE) versus placebo) reduced cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization, but was associated with increased atrial fibrillation/atrial flutter (AF) hospitalization (3.1% IPE versus 2.1% placebo; P=0.004). Methods and Results We performed post hoc efficacy and safety analyses of patients with or without prior AF (before randomization) and with or without in-study time-varying AF hospitalization to assess relationships of IPE (versus placebo) and outcomes. In-study AF hospitalization event rates were higher in patients with prior AF (12.5% versus 6.3%, IPE versus placebo; P=0.007) versus without prior AF (2.2% versus 1.6%, IPE versus placebo; P=0.09). Serious bleeding rates trended higher in patients with (7.3% versus 6.0%, IPE versus placebo; P=0.59) versus without prior AF (2.3% versus 1.7%, IPE versus placebo; P=0.08). With IPE, serious bleeding trended higher regardless of prior AF (interaction P value [Pint]=0.61) or postrandomization AF hospitalization (Pint=0.66). Patients with prior AF (n=751, 9.2%) versus without prior AF (n=7428, 90.8%) had similar relative risk reductions of the primary composite and key secondary composite end points with IPE versus placebo (Pint=0.37 and Pint=0.55, respectively). Conclusions In REDUCE-IT, in-study AF hospitalization rates were higher in patients with prior AF especially in those randomized to IPE. Although serious bleeding trended higher in those randomized to IPE versus placebo over the course of the study, serious bleeding was not different regardless of prior AF or in-study AF hospitalization. Patients with prior AF or in-study AF hospitalization had consistent relative risk reductions across primary, key secondary, and stroke end points with IPE. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01492361; Unique Identifier: NCT01492361.

Alignment of spatial transcriptomics data using diffeomorphic metric mapping

Abstract: Spatial transcriptomics (ST) technologies enable high throughput gene expression characterization within thin tissue sections. However, comparing spatial observations across sections, samples, and technologies remains challenging. To address this challenge, we developed STalign to align ST datasets in a manner that accounts for partially matched tissue sections and other local non-linear distortions using diffeomorphic metric mapping. We apply STalign to align ST datasets within and across technologies as well as to align ST datasets to a 3D common coordinate framework. We show that STalign achieves high gene expression and cell-type correspondence across matched spatial locations that is significantly improved over manual and landmark-based affine alignments. Applying STalign to align ST datasets of the mouse brain to the 3D common coordinate framework from the Allen Brain Atlas, we highlight how STalign can enable the interrogation of compositional heterogeneity across anatomical structures. STalign is available as an open-source Python toolkit at https://github.com/JEFworks-Lab/STalign and as supplementary software with additional documentation and tutorials available at https://jef.works/STalign.

Association between contrast sensitivity and physical function in cognitively healthy older adults: the Brain Network and Mobility Function Study.

Abstract: BACKGROUND To evaluate whether contrast sensitivity is associated with lower extremity physical function in cognitively intact older adults. METHODS Cross-sectional analysis of the relationship of binocular and worse eye log contrast sensitivity (LCS) to expanded Short Physical Performance Battery (eSPPB) and its components (gait speed, narrow walking speed, chair stand pace, balance) in 192 cognitively health older adults. The association of LCS with postural sway and gait were also tested with tasks that further challenged functional reserve. RESULTS Mean age was 76.4 years with 56% identifying as female and over 98.5% having good corrected visual acuity. Lower LCS was significantly associated with worse performance on the eSPPB, 4-M gait speed, narrow walking speed, and balance time in unadjusted and adjusted models. The relationship between worse eye LCS and larger postural sway was three times greater on a foam surface (Beta 1.07, 95% CI (0.35, 1.80)) than firm surface (Beta 0.35, 95% CI (0.05, 0.65)), and both were robust to adjustment for confounders; similar findings were observed with binocular LCS. Lower binocular LCS had a greater decremental effect on gait velocity during the fast pace (Beta -0.58, 95% CI (-0.90, -0.27)) than usual pace (Beta -0.39 (-0.63, -0.15)) gait task. CONCLUSIONS These findings suggest that cognitively unimpaired older adults without significant visual acuity impairment can have subtle preclinical deficits in contrast sensitivity and physical function that could place them at risk of mobility and balance issues. Future studies should determine whether this subset of older adults may benefit from targeted intervention to prevent disability.

A Universal Method for Crossing Molecular and Atlas Modalities using Simplex-Based Image Varifolds and Quadratic Programming

Abstract: This paper explicates a solution to the problem of building correspondences between molecular-scale transcriptomics and tissue-scale atlases. The central model represents spatial transcriptomics as generalized functions encoding molecular position and high-dimensional transcriptomic-based (gene, cell type) identity. We map onto low-dimensional atlas ontologies by modeling each atlas compartment as a homogeneous random field with unknown transcriptomic feature distribution. The algorithm presented solves simultaneously for the minimizing geodesic diffeomorphism of coordinates and latent atlas transcriptomic feature fractions by alternating LDDMM optimization for coordinate transformations and quadratic programming for the latent transcriptomic variables. We demonstrate the universality of the algorithm in mapping tissue atlases to gene-based and cell-based MERFISH datasets as well as to other tissue scale atlases. The joint estimation of diffeomorphisms and latent feature distributions allows integration of diverse molecular and cellular datasets into a single coordinate system and creates an avenue of comparison amongst atlas ontologies for continued future development.