Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy

Introduction: Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods: We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results: CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions: Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE

Increased Systemic Th17 Cytokines Are Associated with Diastolic Dysfunction in Children and Adolescents with Diabetic Ketoacidosis

Diastolic dysfunction suggestive of diabetic cardiomyopathy is established in children with T1DM, but its pathogenesis is not well understood. We studied the relationships of systemic inflammatory cytokines/chemokines and cardiac function in 17 children with T1DM during and after correction of diabetic ketoacidosis (DKA). Twenty seven of the 39 measured cytokines/chemokines were elevated at 6–12 hours into treatment of DKA compared to values after DKA resolution. Eight patients displayed at least one parameter of diastolic abnormality (DA) during acute DKA. Significant associations were present between nine of the cytokine/chemokine levels and the DA over time. Interestingly, four of these nine interactive cytokines (GM-CSF, G-CSF, IL-12p40, IL-17) are associated with a Th17 mediated cell response. Both the DA and CCL7 and IL-12p40, had independent associations with African American patients. Thus, we report occurrence of a systemic inflammatory response and the presence of cardiac diastolic dysfunction in a subset of young T1DM patients during acute DKA

A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation.

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Validation of the PiezoRx® Step Count and Moderate to Vigorous Physical Activity Times in Free Living Conditions in Adults: A Pilot Study

International Journal of Exercise Science 11(7): 541-551, 2018. The purpose of the study was to: 1) Validate the PiezoRx® for steps and intensity related physical activity in free-living conditions compared to the criterion measure. 2) Compare PiezoRx®’s steps and intensity related physical activity to physiological assessments. 3) To assess the utility of the PiezoRx® in a subsample of participants. Thirty-nine participants consisting of 28 females aged 54.9±10.6 (33-74) years and 11 males aged 63.9±10.9 (44-80) years wore the PiezoRx® physical activity monitor and the ActiGraph® accelerometer for one full week and completed a physical assessment. A subsample (n=24) wore the PiezoRx® for an additional two weeks and completed a questionnaire regarding usability. The PiezoRx® had strong correlations to the ActiGraph® for step count (r=0.88; p\u3c0.001), moderate-vigorous physical activity (MVPA) (r=0.70; p\u3c0.001), and sedentary activity (r=0.93; p\u3c0.001) in the 1-week monitoring period. The PiezoRx®’s steps/day and MVPA/week were negatively correlated (p\u3c0.001) to body mass index and waist circumference, and positively correlated (p\u3c0.05) to aerobic fitness, pushups, and 30 second sit-to-stand. Within the subsample who completed the additional two-week monitoring, 75% of participants reported that the PiezoRx® increased their physical activity. In conclusion, The PiezoRx® appears to be a valid measure of free-living PA compared to accelerometry. Because of the correlations of the PiezoRx®’s steps/day and MVPA/week to anthropometric, musculoskeletal and aerobic fitness these PA measures may be valuable objective surrogates to use in clinical or professional practice for physical health

A Pilot Study: Validity and Reliability of the CSEP-PATH PASB-Q and a new Leisure Time Physical Activity Questionnaire to Assess Physical Activity and Sedentary Behaviors

The purpose of this study was to evaluate the accuracy of two newly developed PA questionnaires: the Canadian Society for Exercise Physiology (CSEP) Physical Activity and Sedentary Behavior Questionnaire (PASB-Q) and a newly modified Leisure Time Physical Activity Questionnaire (mLTPA-Q). These questionnaires were compared to objective measurements of physical activity and fitness (accelerometry and physiological assessments) in 35 adults, before and after a week of daily living activity. Objectively measured moderate-to-vigorous intensity aerobic physical activity (MVPA) was moderately correlated with the PASB-Q’s physical activity vital sign (PAVS) (r=0.50, p=0.004) and the mLTPA-Q (r=0.56, p=0.001). Bland Altman plots suggest minimal bias from self-reported to objective measures of MVPA. The ability of PAVS to accurately distinguish who does and does not achieve Canadian PA guidelines was 83% and 60% respectively, compared to 82% and 73% of the LTPA-Q. Self-reported sedentary time was greatly under-estimated in the PASB-Q compared to the objective measure (6.4±3.5 vs 12.2±1.2 hrs/day). The results of this study suggests the PASB-Q and mLTPA-Q are valid and reliable measures of adult PA and provide reasonable indication of those individuals who meet PA guidelines. Future questionnaire development should take into account the underestimation of time spent engaging in sedentary activities.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Step Rate Thresholds Associated with Moderate and Vigorous Physical Activity in Adults

Adults are recommended to engage in 150 min of moderate (MPA) to vigorous (VPA) aerobic physical activity per week, with the public health message of obtaining 3000 steps in 30 min. There is a paucity of research on step rate thresholds that correspond to absolute MVPA (moderate = 3 METs, vigorous = 6 METs) with no research evaluating adult relative MVPA (moderate = 40% VO2max, vigorous = 60% VO2max). Anthropometric differences also influence intensity-related step rate thresholds. The purpose of this study was to identify step rates across a range of walking intensities so that mathematical models incorporating anthropometric factors could be used to identify individualized MVPA step rate thresholds. Forty-three adults (25♀; age = 39.4 ± 15.2 years) completed a staged treadmill walking protocol with pedometers and indirect calorimetry: six-minutes at 2.4, 3.2, 4.0, 5.6, 6.4, 7.2 km/h. Mathematical modelling revealed absolute and relative MPA step rate thresholds of ~100 steps/minute (spm) and ~125 spm, respectively. VPA corresponded to step rates of ~133 spm and ~139 spm for absolute and relative thresholds respectively. The current public message of 3000 steps in 30 min is valid for absolute MPA. However, VPA is achieved at higher thresholds than previously reported, more than 130 spm for healthy adults

30 Year Trends of Reduced Physical Fitness in Undergraduate Students Studying Human Movement

The physical fitness of Canadian adults has decreased over the past 30 years, while sedentary time has increased. However, it is unknown if university students studying human movement exhibit similar population declines. Physical fitness (i.e., anthropometrics, musculoskeletal fitness, and aerobic fitness) and habitual activity (e.g., physical activity, stationary time, etc.) was measured in a cohort of kinesiology students (Post30; 2010–2016; n = 129 males, 224 females) using standardized fitness testing and accelerometry, respectively. Physical fitness was compared to data collected on a cohort of students from the same institution and program, 30 years prior (i.e., Pre, 1984–1987, n = 103 males, 73 females). Post30 had greater waist circumference (males: 83.6 ± 9.1 cm vs. 77.8 ± 8.3 cm, females: 77.1 ± 9.7 cm vs. 70.3 ± 5.2 cm, both p < 0.001) and lower estimated maximal aerobic fitness (males: 55 ± 11 vs. 63 ± 7, females: 45 ± 10 vs. 50 ± 7 mLO2/kg/min, both, p < 0.001). Compared to Pre, male Post30 vertical jump (53.6 ± 10.2 vs. 57.0 ± 8.4 cm, p = 0.04) and female Post30 broad jump (178.7 ± 22.1 vs. 186.0 ± 15.5 cm, p < 0.001) were lower. A subsample (n = 65) of Post30 whose habitual activity was assessed, met the aerobic portion of Canadian physical activity guidelines (~400 min/week), but spent excessive amounts of time stationary (10.7 h/day). Current kinesiology students may not be immune to population decreases in physical fitness. Relative to previous group of students interested in movement, fitness was lower in our sample, potentially attributed to excessive stationary time. Regular assessment of physical fitness in kinesiology curriculums may be valuable to understand these declining trends in undergraduate students that mimic population declines in fitness