The effect of postural orientation on body composition and total body water estimates produced by smartwatch bioelectrical impedance analysis: an intra- and inter-device evaluation.

Advances in wearable technologies now allow modern smartwatches to collect body composition estimates through bioelectrical impedance techniques embedded within their design. However, this technique is susceptible to increased measurement error when postural changes alter body fluid distribution. The purpose of this study was to evaluate the effects of postural orientation on body composition and total body water (TBW) estimates produced by smartwatch bioelectrical impedance analysis (SWBIA) and determine its agreement with criterion measures. For this cross-sectional evaluation, 117 (age: 21.4±3.0 y; BMI: 25.3±5.7 kg/m2) participants (F:69, M:48) completed SWBIA measurements while in the seated, standing, and supine positions, then underwent criterion dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance spectroscopy (BIS) assessments. In the combined sample and females, body fat percent, fat mass, and fat-free mass using SWBIA were significantly different between the supine and standing positions (all p<0.001), though group level agreement with DXA was similar across positions. Supine SWBIA TBW estimates were significantly different between seated and standing estimates (all p≤0.026), but further analyses revealed that this was driven by the supine and seated differences observed in females (p=0.003). SWBIA TBW demonstrated similar group and individual level agreement with BIS across body positions with slight improvements observed during seated and supine assessments for females and males, respectively. SWBIA may demonstrate slight intra- and inter-device differences in body composition and TBW when measured across postural orientations, though further evaluations in external/clinical samples are necessary. While sex/position-specific guidelines may improve precision, these findings highlight the importance of standardized body positioning when using SWBIA.

Gut microbiota metabolically mediate intestinal helminth infection in Zebrafish.

Intestinal helminth parasite (IHP) infection induces alterations in the composition of microbial communities across vertebrates, although how gut microbiota may facilitate or hinder parasite infection remains poorly defined. In this work we utilized a zebrafish model to investigate the relationship between gut microbiota, gut metabolites, and IHP infection. We found that extreme disparity in zebrafish parasite infection burden is linked to the composition of the gut microbiome, and that changes in the gut microbiome are associated with variation in a class of endogenously-produced signaling compounds, N-acylethanolamines, that are known to be involved in parasite infection. Using a statistical mediation analysis, we uncovered a set of gut microbes whose relative abundance explains the association between gut metabolites and infection outcomes. Experimental investigation of one of the compounds in this analysis reveals salicylaldehyde, which is putatively produced by the gut microbe Pelomonas, as a potent anthelmintic with activity against Pseudocapillaria tomentosa egg hatching, both in vitro and in vivo. Collectively, our findings underscore the importance of the gut microbiome as a mediating agent in parasitic infection and highlights specific gut metabolites as tools for the advancement of novel therapeutic interventions against IHP infection.

Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid ß-oxidation. Mutations in either HADHA and HADHB, which encode the TFPα and ß subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting cardiolipin metabolism might be dependent on patient genotype.

Epigenetic Signatures of Asthma: A Comprehensive Study of DNA Methylation and Clinical Markers.

Background: Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma. The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood samples from 319 participants. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 of these individuals. Principal component analysis (PCA) on the clinical markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates. Results: 221 unique CpGs reached genome-wide significance at timepoint 1 (T1) after Bonferroni correction. PC7 accounted for the majority of associations (204), which correlated with loadings of eosinophil counts and immunoglobulin levels. Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint (T2) identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points (271 in total) yielded a correlation of 0.81. Conclusion: We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to using this robust DNA methylation profile as a new, stable biomarker for asthma.

RECORD, a high-throughput, customizable system that unveils behavioral strategies leveraged by rodents during foraging-like decision-making.

Translational studies benefit from experimental designs where laboratory organisms use human-relevant behaviors. One such behavior is decision-making, however studying complex decision-making in rodents is labor-intensive and typically restricted to two levels of cost/reward. We design a fully automated, inexpensive, high-throughput framework to study decision-making across multiple levels of rewards and costs: the REward-COst in Rodent Decision-making (RECORD) system. RECORD integrates three components: 1) 3D-printed arenas, 2) custom electronic hardware, and 3) software. We validated four behavioral protocols without employing any food or water restriction, highlighting the versatility of our system. RECORD data exposes heterogeneity in decision-making both within and across individuals that is quantifiably constrained. Using oxycodone self-administration and alcohol-consumption as test cases, we reveal how analytic approaches that incorporate behavioral heterogeneity are sensitive to detecting perturbations in decision-making. RECORD is a powerful approach to studying decision-making in rodents, with features that facilitate translational studies of decision-making in psychiatric disorders.

Transnational grieving: The lived experience of Overseas Filipino Workers who lost their loved ones due to COVID-19.

This study aimed to gain an insight into the lived experience of Overseas Filipino Workers (OFWs) who lost their family members due to COVID-19 during the lockdown in 2020. Five OFWs volunteered to participate in this study and underwent online semi-structured interviews. An interpretative phenomenological approach guided the data analysis, through which four major themes were derived: (1) experiencing the emotional strains of unexpected death while physically distant; (2) enduring the absence of traditional mourning rituals; (3) managing grief from a distance; and (4) finding closure through physical and symbolic presence. These findings shed light on how OFWs experienced loss and grief during the lockdown, as well as how they coped amidst the distance and eventually finding a degree of closure.

Near-infrared reactance spectroscopy-derived visceral adipose tissue for the assessment of metabolic syndrome in a multi-ethnic sample of young adults.

OBJECTIVES: Visceral adipose tissue (VAT) is highly associated with metabolic syndrome (MetS), which is rapidly increasing in young adults. However, accessible VAT measurement methods are limited, restricting the use of VAT in early detection. This cross-sectional study sought to determine if near-infrared reactance spectroscopy (NIRS)-derived VAT (VATNIRS) was associated with MetS in a multi-ethnic sample of young adults. METHODS: A total of 107 male and female (F:62, M:45) participants (age: 23.0 ± 4.3y; BMI: 27.1 ± 6.6 kg/m2) completed measurements of fasting blood pressure, blood glucose (FBG), blood lipids, and anthropometric assessments including waist circumference and VATNIRS. MetS severity (MetSindex) was calculated from the aforementioned risk factors using sex and race-specific equations. RESULTS: VATNIRS was higher in participants with, and at risk for, MetS compared to those with lower risks (all p < .001). VATNIRS was positively associated with MetSindex for all groups (all p < .001). VATNIRS showed positive associations with systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP), LDL-C and LDL-C-related biomarkers, and FBG; and negative associations with HDL-C and HDL-C-to-total cholesterol ratio (all p < .050). Associations between VATNIRS and blood pressure for females, and LDL-C and LDL-C-related biomarkers for males, were nonsignificant (all p > .050). VATNIRS was positively associated with DBP in African-American participants, and SBP in White participants, resulting in positive associations with MAP for both groups (all p < .050). CONCLUSIONS: VATNIRS is associated with MetS and individual MetS risks factors in a multi-ethnic sample of young adults; providing a noninvasive, cost-effective, portable, and accessible method that may assist in the early detection of MetS and other cardiometabolic abnormalities.

Accumulation of Per- and Polyfluoroalkyl Substances (PFAS) in Coastal Sharks from Contrasting Marine Environments: The New York Bight and The Bahamas.

Per- and polyfluoroalkyl substances (PFAS) enter the marine food web, accumulate in organisms, and potentially have adverse effects on predators and consumers of seafood. However, evaluations of PFAS in meso-to-apex predators, like sharks, are scarce. This study investigated PFAS occurrence in five shark species from two marine ecosystems with contrasting relative human population densities, the New York Bight (NYB) and the coastal waters of The Bahamas archipelago. The total detected PFAS (∑PFAS) concentrations in muscle tissue ranged from 1.10 to 58.5 ng g-1 wet weight, and perfluorocarboxylic acids (PFCAs) were dominant. Fewer PFAS were detected in Caribbean reef sharks (Carcharhinus perezi) from The Bahamas, and concentrations of those detected were, on average, ∼79% lower than in the NYB sharks. In the NYB, ∑PFAS concentrations followed: common thresher (Alopias vulpinus) > shortfin mako (Isurus oxyrinchus) > sandbar (Carcharhinus plumbeus) > smooth dogfish (Mustelus canis). PFAS precursors/intermediates, such as 2H,2H,3H,3H-perfluorodecanoic acid and perfluorooctanesulfonamide, were only detected in the NYB sharks, suggesting higher ambient concentrations and diversity of PFAS sources in this region. Ultralong-chain PFAS (C ≥ 10) were positively correlated with nitrogen isotope values (δ15N) and total mercury in some species. Our results provide some of the first baseline information on PFAS concentrations in shark species from the northwest Atlantic Ocean, and correlations between PFAS, stable isotopes, and mercury further contextualize the drivers of PFAS occurrence.

Characterization of two affinity matured Anti-Yersinia pestis F1 human antibodies with medical countermeasure potential.

Yersinia pestis, the causative agent of plague and a biological threat agent, presents an urgent need for novel medical countermeasures due to documented cases of naturally acquired antibiotic resistance and potential person-to-person spread during a pneumonic infection. Immunotherapy has been proposed as a way to circumvent current and future antibiotic resistance. Here, we describe the development and characterization of two affinity matured human antibodies (αF1Ig AM2 and αF1Ig AM8) that promote survival of mice after exposure to aerosolized Y. pestis. We share details of the error prone PCR and yeast display technology-based affinity maturation process that we used. The resultant matured antibodies have nanomolar affinity for Y. pestis F1 antigen, are produced in high yield, and are resilient to 37°C stress for up to 6 months. Importantly, in vitro assays using a murine macrophage cell line demonstrated that αF1Ig AM2 and αF1Ig AM8 are opsonic. Even more importantly, in vivo studies using pneumonic plague mouse models showed that 100% of the mice receiving 500 µg of IgGs αF1Ig AM2 and αF1Ig AM8 survived lethal challenge with aerosolized Y. pestis CO92. Combined, these results provide evidence of the quality and robustness of αF1Ig AM2 and αF1Ig AM8 and support their development as potential medical countermeasures against plague.

The development of a dexamethasone challenge model for evaluating feed additives in sheep.

OBJECTIVE: To develop an accessible ruminant immune challenge model for rapid in vivo assessments of feed additives. ANIMALS: 60 hair-breed ram lambs. METHODS: Sheep were randomly assigned to 1 of 4 treatments: treatment 1, not immunosuppressed, control fed (n = 12); treatment 2, immunosuppressed, supplemented with a yeast and botanical extract (n = 18); treatment 3, immunosuppressed, supplemented with a blend of natural aluminosilicates and yeast components (n = 18); and treatment 4, immunosuppressed, control fed (n = 12). Twice-daily injections of dexamethasone (Dex; 0.1 mg/kg bodyweight, SC) were used to induce immunosuppression throughout the study (from September 25, 2020, to November 2, 2020). All sheep were immunized with keyhole limpet hemocyanin (KLH) on days 0 and 14 and injected with heat-aggregated KLH, ID, to induce a skin induration on day 15. Measurements included body weight (BW), average daily gain (ADG), CBC, and skin induration diameter. RESULTS: Dex treatment resulted in reduced BW and ADG that was not mitigated by either feed additive. Dex reduced lymphocyte percentage, RBC count, hemoglobin, hematocrit, and skin induration diameter and increased concentrations of granulocytes and granulocyte percentage. Effects on hematocrit, hemoglobin, RBC, and skin induration diameter were mitigated with the addition of feed additives. CLINICAL RELEVANCE: The described model is a tool to evaluate the ability of feed additives to mitigate the immunosuppressive effects of Dex.

Hemodynamic responses to the cold pressor test in individuals with metabolic syndrome: a case-control study in a multiracial sample of adults.

Previous research shows that exercise pressor and metaboreflex responses are significantly exaggerated in individuals with metabolic syndrome, but it is unclear if these exaggerated responses extend to the cold pressor test (CPT). This study tested the hypothesis that, contrary to previously reported exaggerated responses during exercise, CPT responses would not be significantly exaggerated in individuals with MetS compared to matched controls. Eleven individuals with MetS and eleven control participants matched by age, race, sex, and ethnicity completed a cardiometabolic prescreening and a CPT. Each CPT required participants to immerse their hand in ice water for two minutes while beat-by-beat blood pressure, heart rate (HR), and leg blood flow (LBF) were continuously measured. Leg vascular conductance (LVC) was calculated as LBF divided by mean arterial pressure (MAP). The precent changes in MAP, systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, LBF, and LVC were compared across time (BL vs. Minutes 1 and 2 of CPT) and between groups (MetS vs. Control) using repeated measures analyses of variance. As expected, MAP (f = 32.11, p < 0.001), SBP (f = 23.18, p < 0.001), DBP (f = 40.39, p < 0.001), and HR (f = 31.81, p < 0.001) increased during the CPT, and LBF (f = 4.75, p = 0.014) and LVC (f = 13.88, p < 0.001) decreased. However, no significant main effects of group or group by time interactions were observed (f ≤ 0.391, p ≥ 0.539). These findings indicate that the hemodynamic responses to the CPT are not significantly exaggerated in MetS, and therefore, previous reports of exaggerated exercise pressor and metaboreflex responses in MetS cannot be attributed to generalized sympathetic overexcitability.

Merkel cell carcinoma refractory to anti-PD(L)1: utility of adding ipilimumab for salvage therapy.

Merkel cell carcinoma (MCC) incidence has risen to approximately 3,000 cases annually in the USA. Although anti-programmed cell death (ligand) 1 (PD-(L)1) agents are now the first-line treatment for advanced MCC, approximately 50% of such patients do not persistently benefit. In PD-(L)1-refractory cases, ipilimumab (anti-cytotoxic T lymphocyte antigen-4) is often added; however, the extent of the clinical benefit of this combination is controversial. We identified one prospective study, three retrospective studies, and three case reports regarding this combination in refractory MCC. The aggregate response rate from retrospective studies was 32% (13 of 41 patients) with 4 complete responses (CR) and 9 partial responses (PR). In the prospective study, the response rate was very similar at 31% (8 of 26 patients; 4 CR, 4 PR). Response durability was highly variable (range 2 to >43 months), with patients achieving CR having greater durability. Immune-related adverse events (irAEs) were ≥grade III in 29% (retrospective cohort, N=41) and 36% (prospective cohort, N=50). While these aggregate data indicate adding ipilimumab should be considered in this setting, many patients with refractory MCC are ineligible due to comorbidities/irAEs, and approximately 70% will not benefit from this regimen. There is thus a significant unmet need in PD-(L)1-refractory MCC and clinical trials in this setting should be encouraged.

Network resonance and the auditory steady state response.

The auditory steady state response (ASSR) arises when periodic sounds evoke stable responses in auditory networks that reflect the acoustic characteristics of the stimuli, such as the amplitude of the sound envelope. Larger for some stimulus rates than others, the ASSR in the human electroencephalogram (EEG) is notably maximal for sounds modulated in amplitude at 40 Hz. To investigate the local circuit underpinnings of the large ASSR to 40 Hz amplitude-modulated (AM) sounds, we acquired skull EEG and local field potential (LFP) recordings from primary auditory cortex (A1) in the rat during the presentation of 20, 30, 40, 50, and 80 Hz AM tones. 40 Hz AM tones elicited the largest ASSR from the EEG acquired above auditory cortex and the LFP acquired from each cortical layer in A1. The large ASSR in the EEG to 40 Hz AM tones was not due to larger instantaneous amplitude of the signals or to greater phase alignment of the LFP across the cortical layers. Instead, it resulted from decreased latency variability (or enhanced temporal consistency) of the 40 Hz response. Statistical models indicate the EEG signal was best predicted by LFPs in either the most superficial or deep cortical layers, suggesting deep layer coordinators of the ASSR. Overall, our results indicate that the recruitment of non-uniform but more temporally consistent responses across A1 layers underlie the larger ASSR to amplitude-modulated tones at 40 Hz.

Vertebral body collapse after spine stereotactic body radiation therapy: a single-center institutional experience.

BACKGROUND: Spine stereotactic body radiation therapy (SBRT) for the treatment of metastatic disease is increasingly utilized owing to improved pain and local control over conventional regimens. Vertebral body collapse (VBC) is an important toxicity following spine SBRT. We investigated our institutional experience with spine SBRT as it relates to VBC and spinal instability neoplastic score (SINS). PATIENTS AND METHODS: Records of 83 patients with 100 spinal lesions treated with SBRT between 2007 and 2022 were reviewed. Clinical information was abstracted from the medical record. The primary endpoint was post-treatment VBC. Logistic univariate analysis was performed to identify clinical factors associated with VBC. RESULTS: Median dose and number of fractions used was 24 Gy and 3 fractions, respectively. There were 10 spine segments that developed VBC (10%) after spine SBRT. Median time to VBC was 2.4 months. Of the 11 spine segments that underwent kyphoplasty prior to SBRT, none developed subsequent VBC. No factors were associated with VBC on univariate analysis. CONCLUSIONS: The rate of vertebral body collapse following spine SBRT is low. Prophylactic kyphoplasty may provide protection against VBC and should be considered for patients at high risk for fracture.

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis.

Cardiac fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) material resulting in cardiac tissue scarring and dysfunction. While it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains debated. By combining lineage tracing and RNA sequencing, our group made the paradigm-shifting discovery that a subpopulation of resident vascular stem cells residing within the aortic, carotid artery, and femoral aartery adventitia (termed AdvSca1-SM cells) originate from mature vascular smooth muscle cells (SMCs) through an in situ reprogramming process. SMC-to-AdvSca1-SM reprogramming and AdvSca1-SM cell maintenance is dependent on induction and activity of the transcription factor, KLF4. However, the molecular mechanism whereby KLF4 regulates AdvSca1-SM phenotype remains unclear. In the current study, leveraging a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomic approaches, we demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in the setting of Angiotensin II (AngII)-induced cardiac fibrosis. Differentiation was characterized by loss of stemness-related genes, including Klf4 , but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of profibrotic transition of AdvSca1-SM-like cells in human cardiomyopathy. Surprisingly and paradoxically, AdvSca1-SM-specific genetic knockout of Klf4 prior to AngII treatment protected against cardiac inflammation and fibrosis, indicating that Klf4 is essential for the profibrotic response of AdvSca1-SM cells. Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells, but also orchestrates their response to profibrotic stimuli, and may serve as a therapeutic target in cardiac fibrosis.

A kinematically complex multi-articular motor skill for investigating implicit motor learning.

Here we present a task developed to probe implicit learning of a complex motor skill. This task addresses limitations related to task complexity noted in the literature for methods investigating implicit motor learning, namely the serial reaction time task and continuous tracking task. Specifically, the serial reaction time task is limited by the kinematic simplicity of the required movement and the continuous tracing task faces time-on-task confounds and limitations in the control of task difficulty. The task presented herein addresses these issues by employing a kinematically complex multi-articular movement that controls factors that contribute to task difficulty: stimulus animation velocity and trajectory complexity. Accordingly, our objective was to validate the use of this task in probing implicit motor learning, hypothesizing that participants would learn one of the repeating stimuli implicitly. Participants engaged in six blocks of training whereby they first observed and then reproduced a seemingly random complex trajectory. Repeated trajectories were embedded amongst random trajectories. In line with the hypothesis, error for the repeated trajectories was decreased in comparison to that observed for the random trajectories and 73% of participants were unable to identify one of the repeated trajectories, demonstrating the occurrence of implicit learning. While the task requires minor alteration to optimize learning, ultimately the findings underline the task's potential to investigate implicit learning of a complex motor skill.

Measurements of Abdominal Obesity are Associated with Metabolic Syndrome Severity Independent of Hypertensive Phenotype in White but not Black Young Adults.

PURPOSE: This study sought to determine if metabolic syndrome severity (MetSindex) was differentially associated with abdominal obesity based on waist circumference (WC) site and the presentation of hypertensive phenotypes in a group of young White and Black adults. METHODS: A total of 139 young adult (22.5 ± 3.3 years) non-Hispanic White (n = 73) and non-Hispanic Black (n = 66) males and females (M 53, 86 F) completed this cross-sectional evaluation. Participants had their WC measured at three distinct locations along the abdomen which were used to calculate waist-to-hip and waist-to-height ratios. Systolic (SBP) and diastolic blood pressure (DBP) were collected and used to calculate mean arterial pressure (MAP). In addition to traditional metabolic syndrome (MetS) risk factors, BP values were individually used to produce three separate MetSindex scores representing three specific hypertensive phenotypes (MetSSBP, MetSDBP, MetSMAP), and each of these were evaluated against each abdominal obesity estimate. RESULTS: MetSDBP and MetSSBP were significantly higher than all other indices for females (all p ≤ 0.002) and males (all p < 0.001), respectively. MetSDBP was significantly higher than MetSMAP for White females (p = 0.039), and MetSSBP was significantly higher than MetSDBP and MetSMAP (both p < 0.001) for Black males. Standalone and joint estimates of abdominal obesity were uniquely associated with MetSindex across hypertensive phenotypes for White, but not Black males and females. CONCLUSIONS: Specific hypertensive phenotypes may differentially determine MetSindex, but these estimates are not associated with abdominal obesity in young Black adults regardless of measurement location. Healthcare professionals should address this disparity by providing more comprehensive MetS screening procedures for young Black adults. CLINICAL TRIALS REGISTRATION: NCT05885672.