Cancer immunity derailed: PGE2 misconducts cDC1s.

Type 1 conventional dendritic cells (cDC1s) are critical for CD8+ T cell-mediated tumor control. In this issue of Immunity, Bayerl et al.1 expose a mechanism leading to cancer progression where prostaglandin E2 induces dysfunctional cDC1s, which cannot coordinate CD8+ T cell migration and expansion.

Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

Amoebozoan testate amoebae illuminate the diversity of heterotrophs and the complexity of ecosystems throughout geological time.

Heterotrophic protists are vital in Earth's ecosystems, influencing carbon and nutrient cycles and occupying key positions in food webs as microbial predators. Fossils and molecular data suggest the emergence of predatory microeukaryotes and the transition to a eukaryote-rich marine environment by 800 million years ago (Ma). Neoproterozoic vase-shaped microfossils (VSMs) linked to Arcellinida testate amoebae represent the oldest evidence of heterotrophic microeukaryotes. This study explores the phylogenetic relationship and divergence times of modern Arcellinida and related taxa using a relaxed molecular clock approach. We estimate the origin of nodes leading to extant members of the Arcellinida Order to have happened during the latest Mesoproterozoic and Neoproterozoic (1054 to 661 Ma), while the divergence of extant infraorders postdates the Silurian. Our results demonstrate that at least one major heterotrophic eukaryote lineage originated during the Neoproterozoic. A putative radiation of eukaryotic groups (e.g., Arcellinida) during the early-Neoproterozoic sustained by favorable ecological and environmental conditions may have contributed to eukaryotic life endurance during the Cryogenian severe ice ages. Moreover, we infer that Arcellinida most likely already inhabited terrestrial habitats during the Neoproterozoic, coexisting with terrestrial Fungi and green algae, before land plant radiation. The most recent extant Arcellinida groups diverged during the Silurian Period, alongside other taxa within Fungi and flowering plants. These findings shed light on heterotrophic microeukaryotes' evolutionary history and ecological significance in Earth's ecosystems, using testate amoebae as a proxy.

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

GTRpmix: A Linked General Time-Reversible Model for Profile Mixture Models.

Profile mixture models capture distinct biochemical constraints on the amino acid substitution process at different sites in proteins. These models feature a mixture of time-reversible models with a common matrix of exchangeabilities and distinct sets of equilibrium amino acid frequencies known as profiles. Combining the exchangeability matrix with each profile generates the matrix of instantaneous rates of amino acid exchange for that profile. Currently, empirically estimated exchangeability matrices (e.g. the LG matrix) are widely used for phylogenetic inference under profile mixture models. However, these were estimated using a single profile and are unlikely optimal for profile mixture models. Here, we describe the GTRpmix model that allows maximum likelihood estimation of a common exchangeability matrix under any profile mixture model. We show that exchangeability matrices estimated under profile mixture models differ from the LG matrix, dramatically improving model fit and topological estimation accuracy for empirical test cases. Because the GTRpmix model is computationally expensive, we provide two exchangeability matrices estimated from large concatenated phylogenomic-supermatrices to be used for phylogenetic analyses. One, called Eukaryotic Linked Mixture (ELM), is designed for phylogenetic analysis of proteins encoded by nuclear genomes of eukaryotes, and the other, Eukaryotic and Archaeal Linked mixture (EAL), for reconstructing relationships between eukaryotes and Archaea. These matrices, combined with profile mixture models, fit data better and have improved topology estimation relative to the LG matrix combined with the same mixture models. Starting with version 2.3.1, IQ-TREE2 allows users to estimate linked exchangeabilities (i.e. amino acid exchange rates) under profile mixture models.

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells.

IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1 receptor was elevated on murine memory and human naive Treg subsets. IL-2 and IGF1 promoted PI3K/Akt signaling in Tregs, inducing thymically-derived Treg expansion beyond either agent alone in NOD mice. Increased populations of murine Tregs of naive or memory, as well as CD5lo polyclonal or CD5hi likely self-reactive, status were also observed. Expansion was attributed to increased IL-2Rγ subunit expression on murine Tregs exposed to IL-2 and IGF1 as compared with IL-2 or IGF1 alone. Assessing translational capacity, incubation of naive human CD4+ T cells with IL-2 and IGF1 enhanced thymically-derived Treg proliferation in vitro, without the need for TCR ligation. We then demonstrated that IGF1 and IL-2 or IL-7, which is also IL-2Rγ-chain dependent, can be used to induce proliferation of genetically engineered naive human Tregs or T conventional cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive homeostatic T cell expansion, both in vitro and in vivo, for cellular therapeutics and ex vivo gene editing.

Isolation of Diverse Simian Arteriviruses Causing Hemorrhagic Disease.

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Poor Diagnostic Reproducibility in the Identification of Nonconventional Dysplasia in Colitis Impacts the Application of Histologic Stratification Tools.

Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.

Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials.

OBJECTIVES: Acute anterior uveitis ('uveitis') is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management. We report pooled analyses of uveitis incidence in patients receiving bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, from phase 2b/3 trials. METHODS: Data were pooled for patients receiving BKZ 160 mg or placebo in the double-blind treatment period of the phase 3 BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and BE MOBILE 2 (NCT03928743; radiographic axSpA) trials. Data were separately pooled for patients treated with at least one BKZ dose in the BE MOBILE trials and their ongoing open-label extension (OLE; NCT04436640), and the phase 2b BE AGILE trial (NCT02963506; radiographic axSpA) and its ongoing OLE (NCT03355573). Uveitis rates and exposure-adjusted incidence rates (EAIR)/100 patient-years (PYs) are reported. RESULTS: In the BE MOBILE 1 and 2 double-blind treatment period, 0.6% (2/349) of patients receiving BKZ experienced uveitis vs 4.6% (11/237) receiving placebo (nominal p=0.001; EAIR (95% CI): 1.8/100 PYs (0.2 to 6.7) vs 15.4/100 PYs (95% CI 7.7 to 27.5)). In patients with history of uveitis, EAIR was lower in patients receiving BKZ (6.2/100 PYs (95% CI 0.2 to 34.8); 1.9%) vs placebo (70.4/100 PYs (95% CI 32.2 to 133.7); 20.0%; nominal p=0.004). In the phase 2b/3 pool (N=848; BKZ exposure: 2034.4 PYs), EAIR remained low (1.2/100 PYs (95% CI 0.8 to 1.8)). CONCLUSIONS: Bimekizumab, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.

PhyloFisher: A phylogenomic package for resolving eukaryotic relationships.

Phylogenomic analyses of hundreds of protein-coding genes aimed at resolving phylogenetic relationships is now a common practice. However, no software currently exists that includes tools for dataset construction and subsequent analysis with diverse validation strategies to assess robustness. Furthermore, there are no publicly available high-quality curated databases designed to assess deep (>100 million years) relationships in the tree of eukaryotes. To address these issues, we developed an easy-to-use software package, PhyloFisher (https://github.com/TheBrownLab/PhyloFisher), written in Python 3. PhyloFisher includes a manually curated database of 240 protein-coding genes from 304 eukaryotic taxa covering known eukaryotic diversity, a novel tool for ortholog selection, and utilities that will perform diverse analyses required by state-of-the-art phylogenomic investigations. Through phylogenetic reconstructions of the tree of eukaryotes and of the Saccharomycetaceae clade of budding yeasts, we demonstrate the utility of the PhyloFisher workflow and the provided starting database to address phylogenetic questions across a large range of evolutionary time points for diverse groups of organisms. We also demonstrate that undetected paralogy can remain in phylogenomic "single-copy orthogroup" datasets constructed using widely accepted methods such as all vs. all BLAST searches followed by Markov Cluster Algorithm (MCL) clustering and application of automated tree pruning algorithms. Finally, we show how the PhyloFisher workflow helps detect inadvertent paralog inclusions, allowing the user to make more informed decisions regarding orthology assignments, leading to a more accurate final dataset.

Isolation of Naegleria lustrarea n. sp. (Excavata, Discoba, Heterolobosea) from the feces of Ambystoma annulatum (Ringed Salamander) in Northwest Arkansas.

The salamander, Ambystoma annulatum, is considered a "species of special concern" in the state of Arkansas, USA, due to its limited geographic range, specialized habitat requirements and low population size. Although metazoan parasites have been documented in this salamander species, neither its native protists nor microbiome have yet been evaluated. This is likely due to the elusive nature and under-sampling of the animal. Here, we initiate the cataloguing of microbial associates with the identification of a new heterlobosean species, Naegleria lustrarea n. sp. (Excavata, Discoba, Heterolobosea), isolated from feces of an adult A. annulatum.

Living in the cracks: Two novel genera of Variosea (Amoebozoa) discovered on an urban sidewalk.

Biological soil crusts represent a rich habitat for diverse and complex eukaryotic microbial communities. A unique but extremely common habitat is the urban sidewalk and its cracks that collect detritus. While these habitats are ubiquitous across the globe, little to no work has been conducted to characterize protists found there. Amoeboid protists are major predators of bacteria and other microbial eukaryotes in these microhabitats and therefore play a substantial ecological role. From sidewalk crack soil crusts, we have isolated three naked amoebae with finely tapered subpseudopodia, and a simple life cycle consisting of a trophic amoeba and a cyst stage. Using a holistic approach including light, electron, and fluorescence microscopy as well as phylogenetics using the ribosomal small subunit rRNA gene and phylogenomics using 230 nuclear genes, we find that these amoeboid organisms fail to match any previously described eukaryote genus. However, we determined the amoebae belong to the amoebozoan lineage Variosea based on phylogenetics. The molecular analyses place our isolates in two novel genera forming a grade at the base of the variosean group Protosteliida. These three novel varioseans among two novel genera and species are herein named "Kanabo kenzan" and "Parakanabo toge."

Assessment of Posttransplant Bacteremia Caused by Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacteria Among Kidney Transplant Recipients.

BACKGROUND: Extended-spectrum beta-lactamase-producing gram-negative rods (ESBL-GNR) are a rising cause of bacteremia in kidney transplant recipients (KT). The study purpose was to examine patient mortality, allograft survival, estimated glomerular filtration rate (eGFR) at the end of 1 year, and readmission rates while looking at treatment strategies among KTs with ESBL-GNR and non-ESBL-GNR bacteremia at our institution. METHODS: This study was a retrospective, cohort analysis of KTs with gram-negative bacteremia from January 1, 2020, to December 31, 2021. The primary outcome of the study was mortality. Patient outcomes were assessed for 365 days after positive blood cultures. RESULTS: The study included 63 patients. Of these, 18 (29%) patients had bacteremia caused by an ESBL-GNR and 45 (71%) patients had bacteremia caused by a non-ESBL-GNR. Patient survival at 90 days was 94% in the ESBL-GNR group and 96% in the non-ESBL-GNR group. Ciprofloxacin was the most common antimicrobial therapy at discharge (68.9%) in the non-ESBL-GNR group whereas ertapenem was the most common in the ESBL-GNR group (44.5%). Median eGFR at discharge was 41 mL/min/1.73 m2 in the ESBL-GNR group and 48 mL/min/1.73 m2 in the non-ESBL-GNR group. Ninety-day readmission occurred in 9 (50%) ESBL-GNR patients and 14 (32%) non-ESBL-GNR patients. None of the above comparisons are statistically significant (p > 0.05). Eleven (61%) ESBL-GNR and 2 (4%) non-ESBL-GNR patients used outpatient parenteral antimicrobial therapy (p < 0.001). CONCLUSIONS: Among KTs with ESBL-GNR bacteremia, no significant difference was detected in mortality or allograft function compared to non-ESBL-GNR bacteremia.

Association Between Subclinical Right Ventricular Alterations and Aerobic Exercise Capacity in Type 2 Diabetes.

BACKGROUND: Type 2 Diabetes (T2D) leads to cardiovascular remodeling, and heart failure has emerged as a major complication of T2D. There is a limited understanding of the impact of T2D on the right heart. This study aimed to assess subclinical right heart alterations and their contribution to aerobic exercise capacity (peak VO2) in adults with T2D. METHODS: Single center, prospective, case-control comparison of adults with and without T2D, and no prevalent cardiac disease. Comprehensive evaluation of the left and right heart was performed using transthoracic echocardiography and stress cardiovascular magnetic resonance. Cardiopulmonary exercise testing on a bicycle ergometer with expired gas analysis was performed to determine peak VO2. Between group comparison was adjusted for age, sex, race and body mass index using ANCOVA. Multivariable linear regression including key clinical and left heart variables, was undertaken in people with T2D to identify independent associations between measures of right ventricular (RV) structure and function with peak VO2. RESULTS: 340 people with T2D (median age 64 years, 62% male, mean HbA1c 7.3%) and 66 controls (median age 58 years, 58% male, mean HbA1c 5.5%) were included. T2D participants had markedly lower peak VO2 (adjusted mean 20.3(95% CI: 19.8-20.9) vs. 23.3(22.2-24.5) mL/kg/min, P<0.001) than controls and had smaller left ventricular (LV) volumes and LV concentric remodeling. Those with T2D had smaller RV volumes (indexed RV end-diastolic volume: 84(82-86) vs. 100(96-104) mL/m, P<0.001) with evidence of hyperdynamic RV systolic function (global longitudinal strain: 26.3(25.8-26.8) vs. 23.5(22.5-24.5) %, P<0.001) and impaired RV relaxation (longitudinal peak early diastolic strain rate: 0.77(0.74-0.80) vs. 0.92(0.85-1.00) s-1, P<0.001). Multivariable linear regression demonstrated that RV end-diastolic volume (ß=-0.342, P=0.004) and RV cardiac output (ß=0.296, P=0.001), but not LV parameters, were independent determinants of peak VO2. CONCLUSIONS: In T2D, markers of RV remodeling are associated with aerobic exercise capacity, independent of left heart alterations.

Ethnic differences in cardiac structure and function assessed by MRI in healthy South Asian and White European people: A UK Biobank Study.

BACKGROUND: Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI (CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people. METHODS: Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared. RESULTS: 121 matched pairs (77 male/44 female, mean age 58 ± 8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females. CONCLUSIONS: Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.

Toward Gaussian Process Regression Modeling of a Urea Force Field.

FFLUX is a next-generation, machine-learnt force field built on three cornerstones: quantum chemical topology, Gaussian process regression, and (high-rank) multipolar electrostatics. It is capable of performing molecular dynamics with near-quantum accuracy at a lower computational cost than standard ab initio molecular dynamics. Previous work with FFLUX was concerned with water and formamide. In this study, we go one step further and challenge FFLUX to model urea, a larger and more flexible system. In result, we have trained urea models at the B3LYP/aug-cc-pVTZ level of theory, with a mean absolute error of 0.4 kJ mol-1 and a maximum prediction error below 7.0 kJ mol-1. To test their performance in molecular dynamics simulations, two sets of FFLUX geometry optimizations were carried out: 5 dimers corresponding to energy minima and 75 random dimers. The 5 dimers were recovered with a root-mean-square deviation below 0.1 Å with respect to their ab initio references. Out of the 75 random dimers, 68% converged to the qualitatively same dimer as those obtained at the ab initio level. Furthermore, we have ranked the 5 FFLUX-optimized dimers in the order of their relative FFLUX single-point energies and compared them with the ab initio method. The energy ranking fully agreed but for one crossover between two successive minima. Finally, we have demonstrated the importance of geometry-dependent (i.e., flexible) multipole moments, showing that the lack of multipole moment flexibility can lead to average errors in the total intermolecular electrostatic energy of more than 2 orders of magnitude.

Transferability of Buckingham Parameters for Short-Range Repulsion between Topological Atoms.

The repulsive part of the Buckingham potential, with parameters A and B, can be used to model deformation energies and steric energies. Both are calculated using the interacting quantum atom energy decomposition scheme where the latter is obtained from the former by a charge-transfer-based energy correction. These energies relate to short-range interactions, specifically the deformation of electron density and steric hindrance, respectively, when topological atoms approach each other. In this work, we calculate and fit the energies of carbonyl carbon, carbonyl oxygen, and, where possible, amine nitrogen atoms to the repulsive part of the Buckingham potential for 26 molecules. We find that while the steric energies of all atom pairs studied display exponential behavior with respect to distance, some deformation energy data do not. The obtained parameters are shown to be transferable by calculating root-mean-square errors of fitted potentials with respect to energy data of the same atom in, as far as possible, all other molecules from our data set. We observed that 36% and 10% of these errors were smaller than 4 kJ mol-1 for steric and deformation energy, respectively. Thus, we find that steric energy parameters are more transferable than deformation energy parameters. Finally, we speculate about the physical meaning of the A and B parameters and the implications of the strong exponential and exponential-linear piecewise relationships that we observe between them.

Circulating sphingolipids and relationship to cardiac remodelling before and following a low-energy diet in asymptomatic Type 2 Diabetes.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling. METHODS: Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case-control comparison (fold change > 1.5 and statistical significance p < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored. RESULTS: Twenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling. CONCLUSION: The lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D. TRIAL REGISTRATION: NCT02590822.

Skeletal Muscle Texture Assessment Using Ultrasonography: Comparison with Magnetic Resonance Imaging in Chronic Kidney Disease.

Skeletal muscle dysfunction is common in chronic kidney disease (CKD). Of interest is the concept of "muscle quality," of which measures include ultrasound-derived echo intensity (EI). Alternative parameters of muscle texture, for example, gray level of co-occurrence matrix (GCLM), are available and may circumvent limitations in EI. The validity of EI is limited in humans, particularly in chronic diseases. This study aimed to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Images of the thigh were acquired using a 3 Tesla MRI scanner. Quantification of muscle (contractile), fat (non-contractile), and miscellaneous (connective tissue, fascia) components were estimated. Anatomical rectus femoris cross-sectional area was measured using B-mode 2D ultrasonography. To assess muscle texture, first (i.e., EI)- and second (i.e., GLCM)-order statistical analyses were performed. Fourteen participants with CKD were included (age: 58.0 ± 11.9 years, 50% male, eGFR: 27.0 ± 7.4 ml/min/1.73m2, 55% Stage 4). Higher EI was associated with lower muscle % (quadriceps: ß = -.568, p = .034; hamstrings: ß = -.644, p = .010). Higher EI was associated with a higher fat % in the hamstrings (ß = -.626, p = .017). A higher angular second moment from GLCM analysis was associated with greater muscle % (ß = .570, p = .033) and lower fat % (ß = -.534, p = .049). A higher inverse difference moment was associated with greater muscle % (ß = .610, p = .021 and lower fat % (ß = -.599, p = .024). This is the first study to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Our preliminary findings suggest ultrasound-derived texture analysis provides a novel indicator of reduced skeletal muscle % and thus increased intramuscular fat.