Phenomenological Muscle Constitutive Model With Actin-Titin Binding for Simulating Active Stretching.

The force produced by a muscle depends on its contractile history, yet human movement simulations typically employ muscle models that define the force-length relationship from measurements of fiber force during isometric contractions. In these muscle models, the total force-length curve can have a negative slope at fiber lengths greater than the fiber length at which peak isometric force is produced. This region of negative stiffness can cause numerical instability in simulations. Experiments have found that the steady-state force in a muscle fiber following active stretching is greater than the force produced during a purely isometric contraction. This behavior is called residual force enhancement. We present a constitutive model that exhibits force enhancement, implemented as a hyperelastic material in the febio finite element software. There is no consensus on the mechanisms responsible for force enhancement; we adopt the assumption that the passive fiber force depends on the sarcomere length at the instant that the muscle is activated above a threshold. We demonstrate the numerical stability of our model using an eigenvalue analysis and by simulating a muscle whose fibers are of different lengths. We then use a three-dimensional muscle geometry to verify the effect of force enhancement on the development of stress and the distribution of fiber lengths. Our proposed muscle material model is one of the few models available that exhibits force enhancement and is suitable for simulations of active lengthening. We provide our implementation in febio so that others can reproduce and extend our results.

Staging accuracy in patients with clinical T2N0 gastric cancer: Implications for treatment sequencing.

BACKGROUND: Patients with clinical T2N0 (cT2N0) gastric adenocarcinoma are recommended to undergo either perioperative chemotherapy or upfront resection. If T2N0 disease is pathologically confirmed, patients may be observed without chemotherapy. These guidelines create the possibility of both systemic therapy overuse and underuse depending on clinical staging accuracy. Our objectives were to define factors associated with upstaging after upfront resection and describe the association between postoperative chemotherapy and survival. METHODS: Patients with cT2N0 gastric adenocarcinoma were identified using the National Cancer Database. Factors associated with upstaging were assessed by logistic regression. Survival was assessed using Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Of 4,076 patients undergoing upfront resection for cT2N0 gastric cancer, 1,933 (47.4%) were pathologically upstaged. Patients were more likely to be upstaged if they had >3.0-cm (adjusted odds ratio [aOR] 2.31, 95% confidence interval [CI] 1.97-2.70; P < .001) or poorly differentiated tumors (aOR 2.22, 95% CI 1.89-2.60; P < .001). Patients were less likely to be upstaged if they had distal tumors (aOR 0.77, 95% CI 0.64-0.93; P = .006). Of those pathologically upstaged (n = 1,933), 1,111 (57.4%) received adjuvant chemotherapy that was associated with improved survival (HR 0.55, 95% CI 0.47-0.63; P < .001). Among those not upstaged (n = 2,143), 247 (11.5%) received adjuvant chemotherapy that was not associated with improved survival (HR 0.92, 95% CI 0.70-1.21; P = .54). CONCLUSIONS: Pathologic upstaging after upfront resection in patients with cT2N0 gastric cancer is associated with patient and tumor characteristics. Adjuvant chemotherapy is associated with improved survival only in the patients upstaged at surgery. An upfront surgical approach may be preferred in select patients, especially if avoiding chemotherapy is desired.

The Oral Health Status and Anthropometric Measurements of Children at Early Childhood Development Centers in an Informal Settlement in Pretoria, South Africa.

Objectives: Early childhood caries (ECC) continue to increase, especially among low socioeconomic communities. This study was conducted in an informal settlement comprising mostly foreigners who have settled in the area. Given the limited dental and medical services available to these communities, this study aimed to determine the dental and medical disease profile of these inhabitants. The objective was to determine the oral health status and the body mass index (BMI) of children attending crèches in an informal settlement. Materials and methods: Oral health data, including dental caries (DC), soft tissue lesions, fluorosis, erosion, and trauma, were recorded using the World Health Organization (WHO) recommended methods. The examiners were calibrated, and all examinations took place at the crèches under natural sunlight. The BMI was calculated by a team of dieticians who were blinded to the oral health status. The height and weight were measured by calibrated examiners under standardized conditions. Results: There were a total of 169 participants; the mean age was 4.02 years (±1.13; 1-7) and there was an equal distribution of males and females (49.7% females and 49.3% males). The prevalence of DC was 39.1%, with 19% having 4 or more carious teeth. The mean decayed, missing, and filled teeth (dmft) and plaque scores [Simplified Oral Hygiene Index (OHI-S)] were 1.58 (±2.70) and 0.65 (±0.43), respectively, and the mean dmft score increased with increasing age. The mean d component contributed 99% of the total mean dmft score (1.56). The mean BMI was 15.44, and this decreased significantly (p = 0.009) while the OHI increased significantly (p < 0.001) as the number of carious teeth increased. Conclusion: The prevalence of caries was relatively high, and those with caries had multiple decayed teeth. The d component contributed almost 100% to the mean score, indicating a lack of access to dental care. The mean BMI score was inversely proportional to the number of carious teeth, which could imply that those with caries had difficulty eating. How to cite this article: Bhayat A, Madiba TK, Beeforth M, et al. The Oral Health Status and Anthropometric Measurements of Children at Early Childhood Development Centers in an Informal Settlement in Pretoria, South Africa. Int J Clin Pediatr Dent 2024;17(8):903-906.

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME.

Multicenter Pivotal Study of the Alterra Adaptive Prestent for the Treatment of Pulmonary Regurgitation.

BACKGROUND: A dilated native right ventricular outflow tract (RVOT) presents unique challenges for transcatheter management using balloon-expandable valves. The Alterra Adaptive Prestent was designed to expand transcatheter therapy to treat patients with dilated RVOTs. OBJECTIVES: The aim of this study was to report 2-year outcomes of the main cohort of the ALTERRA (Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying the SAPIEN 3 THV With the Alterra Adaptive Prestent) pivotal trial using the prestent with transcatheter pulmonary valve replacement. METHODS: The prestent device used with the 29 mm SAPIEN 3 transcatheter heart valve (THV) was evaluated for the management of patients with moderate or greater pulmonary valve regurgitation (PR). The primary endpoint was THV dysfunction at 6 months, defined as a nonhierarchical composite of RVOT/pulmonary valve reintervention, moderate or greater total PR on transthoracic echocardiography, and mean RVOT/pulmonary valve gradient 35 mm Hg or greater on transthoracic echocardiography. The primary endpoint and outcomes through 2 years are presented in this analysis. RESULTS: Of 97 patients screened, 60 underwent prestent and THV implantation. There was 1 staged procedure. No patients had THV dysfunction at 6 months. At 2 years, the majority of patients (92.5%) had mild or less PR, with no reports of coronary compression, stent fractures warranting reintervention, or endocarditis. Of the 21 patients (34.4%) who experienced early (days 0-1) arrhythmias, 12 had episodes of nonsustained ventricular tachycardia that resolved with medication. One patient underwent reintervention secondary to an iatrogenic RVOT obstruction; there were no deaths or explantations through 2 years. CONCLUSIONS: The Alterra prestent in combination with the SAPIEN 3 THV has excellent outcomes at 2 years, with no significant valve dysfunction in the main pivotal cohort.

Genome-wide studies define new genetic mechanisms of IgA vasculitis.

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 -25 ) and fine-mapped specific amino-acid risk substitutions in DRß1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 -20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 -09 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .

Measurements of chromatic adaptation and luminous efficiency while wearing colored filters.

The visual system adapts dynamically to stabilize perception over widely varying illuminations. Such adaptation allows the colors of objects to appear constant despite changes in spectral illumination. Similarly, the wearing of colored filters also alters spectral content, but this alteration can be more extreme than typically encountered in nature, presenting a unique challenge to color constancy mechanisms. While it is known that chromatic adaptation is affected by surrounding spatial context, a recent study reported a gradual temporal adaptation effect to colored filters such that colors initially appear strongly shifted but over hours of wear are perceived as closer to an unfiltered appearance. Presently, it is not clear whether the luminance system adapts spatially and temporally like the chromatic system. To address this, spatial and temporal adaptation effects to a colored filter were measured using tasks that assess chromatic and luminance adaptation separately. Prior to and for 1 hour after putting on a pair of colored filters, participants made achromatic and heterochromatic flicker photometry (HFP) settings to measure chromatic and luminance adaptation, respectively. Results showed significant chromatic adaptation with achromatic settings moving closer to baseline settings over 1 hour of wearing the filters and greater adaptation with spatial context. Conversely, there was no significant luminance adaptation and HFP matches fell close to what was predicted photometrically. The results are discussed in the context of prior studies of chromatic and luminance adaptation.

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

BACKGROUND: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aß)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel. METHODS: The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aß40, and Aß42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aß pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers. RESULTS: NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aß pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aß-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aß PET-dependent yearly increases in Aß-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype. CONCLUSIONS: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Incidence and Outcomes of Pregnant Trauma Patients With Positive Urine Toxicology: A Southern California Multicenter Study.

Background: The use of illicit substances during pregnancy has increased 4-fold in the past two decades, negatively impacting both mother and fetus. The rate and clinical outcomes of substance use in pregnant trauma patients (PTPs) are not well studied. We sought to evaluate clinical outcomes of PTPs with positive urine toxicology, hypothesizing a higher rate of in-hospital maternal complications for PTPs with a positive urine toxicology ((+)Utox) compared to those testing negative ((-)Utox). Methods: PTPs (≥18 years old) were included in this multicenter retrospective study between 2016 and 2021. We included patients with known urine toxicology results and compared (+)Utox vs (-)Utox PTPs. Results: From 852 PTPs, 84 (9.8%) had a (+)Utox with the most common illicit substance being THC (57%) followed by methamphetamine (44%). (+)Utox PTPs had higher rates of blunt head injury (9.5% vs 4.2%, P = .028), extremity injury (14.3% vs 6.5%, P = .009), domestic violence (21.4% vs 5.9%, P < .001), suicide attempt (3.6% vs 0.3%, P < .001), and uterine contractions (46% vs 23.5%, P < .001). Abnormal fetal heart tracing, premature rupture of membranes and placental injury were similar between groups (all P > .05). The rate of maternal complications was similar in both groups (all P > .05). Conclusion: In this study, the rate of (+)Utox in PTPs was 9.8%. The (+)Utox group had similar rates of maternal complications but more commonly experienced uterine contractions which may be related to the physiology of drugs such as methamphetamines. PTPs with (+)Utox also more commonly were victims of domestic violence and suicide attempt, which merits further prevention research efforts.

The temporal sequence and reciprocal relationships of frailty, social isolation and loneliness in older adults across 21 years.

BACKGROUND: It is unclear whether social isolation and loneliness may precede frailty status or whether frailty may precipitate social isolation and loneliness. We investigated the reciprocal and temporal sequence of social isolation, loneliness, and frailty among older adults across 21 years. METHODS: We used seven waves of the Longitudinal Aging Study Amsterdam from 2302 Dutch older adults (M = 72.6 years, SD = 8.6, 52.1% female) ages 55 or older. Using random intercept cross-lagged panel models, we investigated between- and within-person associations of social isolation and loneliness with frailty. Frailty was measured using the Frailty Index. Loneliness was measured using the 11-item De Jong Gierveld Loneliness Scale. Social isolation was measured using a multi-domain 6-item scale. RESULTS: Social isolation and loneliness were weakly correlated across waves. At the between-person level, individuals with higher levels of frailty tended to have higher levels of social isolation but not loneliness. At the within-person level, the cross-lagged paths indicated that earlier frailty status predicted future social isolation and loneliness over time. However, prior social isolation was not associated with subsequent frailty except at time point 5 (T5). Loneliness at specific time points (T1, T4 and T6) predicted greater frailty at later time points (T2, T5 and T7). The results also supported reciprocal and contemporaneous relations between social isolation, loneliness and frailty. CONCLUSIONS: Social isolation and loneliness are potential outcomes of frailty. Public health policies and health practitioners should prioritise interventions targeting social connection among older adults with pre-frailty or frailty.

Origin of sandy substrates controlling the distribution of open vegetation ecosystems in Amazonia.

Understanding the role of open vegetation, particularly in white-sand ecosystems (WSE) and savannas, is crucial for elucidating their role in Amazonian biotic diversification. These ecosystems predominantly develop on sandy terrains, suggesting that the geological substrate significantly influences the vegetation upon it. Therefore, the interaction between landscape changes and biotic diversification is closely tied to the dynamics and resilience of these sandy substrates. Current WSE and savannas in lowland Amazonia colonized fluvial sediments deposited during the past 120 ka, with marked synchronicity over the last 23 ka, as shown by optically stimulated luminescence (OSL) and radiocarbon ages of such sandy substrates. In contrast, sandy substrates supporting open vegetation in highland areas, unsuitable for Quaternary sand accumulation, would have persisted beyond the Quaternary, as ancient sedimentary rocks in these areas are prone to developing sandy soils. The current distribution of open vegetation ecosystems in lowland Amazonia is coupled with the deposition and erosion of sandy sediments by Quaternary fluvial systems, while weathering sandy substrates in highland areas serve as long-term and resilient refugia beyond the Quaternary. The contrasting spatiotemporal dynamics of landscape changes in lowland and highland areas has implications for biodiversification or extinction events leading to current biogeography patterns in Amazonia.

Theoretical elucidation of the effect of the linkage and orientation of carbazole and naphthalenediimide on the TADF and RTP propensities.

Thermally activated delayed fluorescence (TADF) and room temperature phosphorescence (RTP) are most promising processes for harvesting triplet excitons in organic light-emitting diodes. In this work, the effect of the linkage between the carbazole (Cz) donor (D) and the naphthalenediimide (NDI) acceptor (A) on the TADF and RTP propensities is elucidated using density functional theory computations employing D-A, D-A-D, D-π-A, and D-π-A-π-D structural designs. The effects of the dihedral angle between the donor and acceptor units on the energy difference between the singlet and triplet excited states (ΔEST), the spin-orbit coupling (SOC) constants, and radiative (kr), intersystem crossing (kISC) and reverse intersystem crossing (kRISC) rates are unravelled. The molecules possessing a direct linkage between Cz and NDI exhibit large ΔEST values due to substantial overlap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). However, the insertion of a phenyl spacer between the Cz and NDI units led to disjoint HOMO and LUMO and consequently resulted in a small ΔEST. Furthermore, the presence of two donors with and without a phenyl spacer on NDI resulted in a high-lying triplet state (T2) that is energetically lower than the lowest singlet excited state (S1), hence providing additional channels to the TADF and RTP processes. Also, the orientation of Cz and NDI in the ortho-positions of the phenyl unit resulted in a T1 state with dominant LE character which led to moderate spin-orbit coupling constants and highest kr rates compared to the analogous meta- and para-linked derivatives. Thus, the ortho-derivatives possessed small ΔEST, charge transfer dominated S1, joint holes and electrons for the T1 state, characteristic of local excitation, high SOC, and promising rISC and kr rates. Overall, the phenyl linked derivatives possess TADF characteristics, while the directly linked analogues show RTP propensity.

Exercise-Associated Muscle Cramps in Ironman-Distance Triathletes Over 3 Decades.

OBJECTIVE: This study aimed to explore associations and trends for athletes experiencing exercise-associated muscle cramps (EAMC) in ultraendurance competitions. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Medical tent data were collected from annual IRONMAN World Championship events. PARTICIPANTS: In total, 10 533 medical records were reviewed among 49 530 race participants from 1989 to 2019. ASSESSMENT OF RISK FACTORS: Athlete demographics data, performance data, and additional medical conditions were examined. MAIN OUTCOME MEASURES: Primary outcome of interest was to compare triathletes with and without EAMC. Secondary outcome was to analyze triathletes with subsequent EAMC. RESULTS: EAMC (N = 2863) occurred in 57.8 per 1000 participants (95% confidence interval = 55.7 to 60.0). The incidence of EAMC did not differ between athlete sex. Athletes with EAMC had greater weight loss but did not differ in serum sodium and serum potassium compared with those without EAMC. Further analysis with a logistic regression analysis revealed that dehydration, exhaustion, hypotension, abdominal pain, headaches, and a previous evaluation for cramping were strongly associated with muscle cramping. The most common treatment for EAMC was intravenous fluids. CONCLUSIONS: Findings from the current study support previous reports that electrolyte abnormalities are not associated with cramping. However, our finding that dehydration is associated with muscle cramping contradicts current literature.

Type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from head and neck cancer patients.

BACKGROUND: Exosomes are closely associated with different aspects of tumor-progression in patients with head and neck squamous cell carcinoma (HNSCC), such as angiogenesis or immune regulation. As extracellular vesicles they are involved in the intercellular communication by transferring their cargo such as proteins and nucleic acids from one cell to another. However, the influence of tumor related plasma-derived exosomes on the polarization and characteristics of monocyte derived macrophages is not fully understood. METHODS: Exosomes were isolated from plasma samples of healthy donors (HD) and HNSCC patients and further evaluated with regard to morphology, size and protein composition via transmission electron microscopy, nanoparticle tracking, western blot analysis and cytokine assays. Differentiation and characteristics of monocyte derived macrophages upon exosome internalization were analyzed using flow cytometry and fluorescence microscopy. Macrophage cytokine secretion patterns were analyzed by human cytokine antibody arrays and ELISA measurements. RESULTS: Our data revealed elevated overall plasma levels of CTLA-4, PD-L1, and TIM-3 as well as elevated exosome-associated CTLA-4, PD-L2, TIM-3, and LAG-3 levels in HNSCC patients compared to HD. Furthermore, we observed a significant type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from HNSCC patients, which could be visualized by fluorescence microcopy of membrane stained exosomes. CONCLUSIONS: The study provides new insights regarding exosome driven pro-tumorigenic immune regulation in the circulation of patients with head and neck cancer and could help to better understand the individual immunologic situation.

Molecular and Functional Cargo of Plasma-Derived Exosomes in Patients with Hereditary Hemorrhagic Telangiectasia.

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder leading to frequent bleeding in several organs. As HHT diagnosis is demanding and depends on clinical criteria, liquid biopsy would be beneficial. Exosomes from biofluids are nano-sized vesicles for intercellular communication. Their cargo and characteristics represent biomarkers for many diseases. Here, exosomes of HHT patients were examined regarding their biosignature. Methods: Exosomes were isolated from the plasma of 20 HHT patients and 17 healthy donors (HDs). The total exosomal protein was quantified, and specific proteins were analyzed using Western blot and antibody arrays. Human umbilical vein endothelial cells (HUVECs) co-incubated with exosomes were functionally examined via immunofluorescence, proliferation, and scratch assay. Results: The levels of the angiogenesis-regulating protein Thrombospondin-1 were significantly higher in HHT compared to HD exosomes. Among HHT, but not HD exosomes, a negative correlation between total exosomal protein and soluble Endoglin (sENG) levels was found. Other exosomal proteins (ALK1, ALK5) and the particle concentration significantly correlated with disease severity parameters (total consultations/interventions, epistaxis severity score) in HHT patients. Functionally, HUVECs were able to internalize both HD and HHT exosomes, inducing a similar change in the F-Actin structure and a reduction in migration and proliferation. Conclusions: This study provided first insights into the protein cargo and function of HHT-derived exosomes. The data indicate changes in sENG secretion via exosomes and reveal exosomal Thrombospondin-1 as a potential biomarker for HHT. Several exosomal characteristics were pointed out as potential liquid biomarkers for disease severity, revealing a possible new way of diagnosis and prognosis of HHT.

Mugen-UMAP: UMAP visualization and clustering of mutated genes in single-cell DNA sequencing data.

BACKGROUND: The application of Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and visualization has revolutionized the analysis of single-cell RNA expression and population genetics. However, its potential in single-cell DNA sequencing data analysis, particularly for visualizing gene mutation information, has not been fully explored. RESULTS: We introduce Mugen-UMAP, a novel Python-based program that extends UMAP's utility to single-cell DNA sequencing data. This innovative tool provides a comprehensive pipeline for processing gene annotation files of single-cell somatic single-nucleotide variants and metadata to the visualization of UMAP projections for identifying clusters, along with various statistical analyses. Employing Mugen-UMAP, we analyzed whole-exome sequencing data from 365 single-cell samples across 12 non-small cell lung cancer (NSCLC) patients, revealing distinct clusters associated with histological subtypes of NSCLC. Moreover, to demonstrate the general utility of Mugen-UMAP, we applied the program to 9 additional single-cell WES datasets from various cancer types, uncovering interesting patterns of cell clusters that warrant further investigation. In summary, Mugen-UMAP provides a quick and effective visualization method to uncover cell cluster patterns based on the gene mutation information from single-cell DNA sequencing data. CONCLUSIONS: The application of Mugen-UMAP demonstrates its capacity to provide valuable insights into the visualization and interpretation of single-cell DNA sequencing data. Mugen-UMAP can be found at https://github.com/tengchn/Mugen-UMAP.

Challenges and Priorities for Children With Congenital Valvar Heart Disease: The Heart Valve Collaboratory.

The Heart Valve Collaboratory is a multidisciplinary, patient-centered community of stakeholders addressing complex problems and embracing innovation to help patients with heart valve disease achieve their fullest potential for health. The Scientific Council is composed of cardiologists, surgeons, ex-officio representatives of the Food and Drug Administration and Centers for Medicare and Medicaid Services, National Heart Lung Blood Institute, and representatives from industry partners. In October 2022, this group convened a workshop that included experts from stakeholder groups to address the unmet and clinical needs of patients with pediatric and congenital heart valve disease. The following document includes the discussion and summary of the current state of valve therapy and the needs being addressed for valve development.

Herbivore diversity effects on Arctic tundra ecosystems: a systematic review.

BACKGROUND: Northern ecosystems are strongly influenced by herbivores that differ in their impacts on the ecosystem. Yet the role of herbivore diversity in shaping the structure and functioning of tundra ecosystems has been overlooked. With climate and land-use changes causing rapid shifts in Arctic species assemblages, a better understanding of the consequences of herbivore diversity changes for tundra ecosystem functioning is urgently needed. This systematic review synthesizes available evidence on the effects of herbivore diversity on different processes, functions, and properties of tundra ecosystems. METHODS: Following a published protocol, our systematic review combined primary field studies retrieved from bibliographic databases, search engines and specialist websites that compared tundra ecosystem responses to different levels of vertebrate and invertebrate herbivore diversity. We used the number of functional groups of herbivores (i.e., functional group richness) as a measure of the diversity of the herbivore assemblage. We screened titles, abstracts, and full texts of studies using pre-defined eligibility criteria. We critically appraised the validity of the studies, tested the influence of different moderators, and conducted sensitivity analyses. Quantitative synthesis (i.e., calculation of effect sizes) was performed for ecosystem responses reported by at least five articles and meta-regressions including the effects of potential modifiers for those reported by at least 10 articles. REVIEW FINDINGS: The literature searches retrieved 5944 articles. After screening titles, abstracts, and full texts, 201 articles including 3713 studies (i.e., individual comparisons) were deemed relevant for the systematic review, with 2844 of these studies included in quantitative syntheses. The available evidence base on the effects of herbivore diversity on tundra ecosystems is concentrated around well-established research locations and focuses mainly on the impacts of vertebrate herbivores on vegetation. Overall, greater herbivore diversity led to increased abundance of feeding marks by herbivores and soil temperature, and to reduced total abundance of plants, graminoids, forbs, and litter, plant leaf size, plant height, and moss depth, but the effects of herbivore diversity were difficult to tease apart from those of excluding vertebrate herbivores. The effects of different functional groups of herbivores on graminoid and lichen abundance compensated each other, leading to no net effects when herbivore effects were combined. In turn, smaller herbivores and large-bodied herbivores only reduced plant height when occurring together but not when occurring separately. Greater herbivore diversity increased plant diversity in graminoid tundra but not in other habitat types. CONCLUSIONS: This systematic review underscores the importance of herbivore diversity in shaping the structure and function of Arctic ecosystems, with different functional groups of herbivores exerting additive or compensatory effects that can be modulated by environmental conditions. Still, many challenges remain to fully understand the complex impacts of herbivore diversity on tundra ecosystems. Future studies should explicitly address the role of herbivore diversity beyond presence-absence, targeting a broader range of ecosystem responses and explicitly including invertebrate herbivores. A better understanding of the role of herbivore diversity will enhance our ability to predict whether and where shifts in herbivore assemblages might mitigate or further amplify the impacts of environmental change on Arctic ecosystems.

Insertable, dual-density dielectric barrier for acoustic pressure level reduction in a high-performance human head-only MRI system.

We report use of a dual-density dielectric barrier surrounding a detachable high-pass radiofrequency (RF) birdcage coil to achieve an order-of-magnitude reduction of acoustic noise in a high-performance head gradient system. The barrier consisted of a 4.5 mm-thick mass-loaded vinyl and a 6 mm-thick polyurethane foam. It was inserted into the radial gap between the birdcage coil and the RF shield in a prototype head-only gradient system at 3 T. More than 9 dBA reduction of sound pressure level was achieved on the average with representative, high acoustic-noise imaging sequences. Increased acoustic damping was apparent from acoustic impulse response functions. High dielectric constant of the mass-loaded vinyl effectively added distributed capacitance to the birdcage coil, lowering the resonance frequency, but not seriously degrading the RF transmission performance. The barrier occupied the radial space normally used for air cooling of the RF coil and the RF shield. The resulting omission of air cooling was found to be acceptable with efficient gradient thermal management and use of a high-resistivity RF shield for eddy current reduction. The proposed method can improve patient experience while preserving image quality in a high-power head-only gradient system.