Environmental metals and birth defects: New approaches to understanding the role of metals in congenital heart defects

Birth defects are a leading cause of infant mortality, and cardiac defects are among the most fatal. The majority of birth defects have no known cause whether environmental, genetic, or a combination of these factors. Toxic metals are likely contributors to birth defects in humans, yet the biological pathways that underlie these relationships remain largely unknown. The objective of this research was to assess the contributions of environmental metals to congenital heart defects using i) an ecologic study to evaluate the relationship between metals and birth defects in North Carolina and ii) an in vitro cardiomyocyte model to identify underlying metalaltered molecular pathways. This research evaluated the associations between arsenic, cadmium, manganese, and lead levels in private well water with the prevalence of specific birth defects using six years of data collected by the North Carolina Birth Defects Monitoring Program. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in census tracts with the highest average metal levels compared to the lowest average metal levels, adjusted for maternal age, race, and education status. We identified relationships between the highest category of arsenic exposure and the prevalence of conotruncal heart defects (PR: 1.3 95%CI: 0.9-1.8) as well as the highest category of manganese exposure and the prevalence of atrioventricular septal heart defects (PR: 1.8 95% CI: 1.1-3.1). The findings suggest an ecologic association between concentrations of metals in drinking water and the prevalence of specific birth defects. Next, we applied an in vitro approach to identify biological pathways that underlie metal-altered signaling in the heart. We exposed human-derived cardiomyocytes to low-level cadmium chloride (0.5 μM) and assessed changes in genome-wide microRNA (miRNA) and messenger RNA (mRNA) expression levels. We identified 8 miRNAs and 31 genes that were differentially expressed in cardiomyocytes exposed to cadmium compared to unexposed controls. A subset of 8 mRNAs were predicted targets of the cadmium-associated miRNAs. We identified miRNA-dependent signaling pathways that were enriched for gene expression, embryonic development, and organismal development. Taken together, the findings contribute to the understanding of potentially preventable environmentally-mediated birth defects.Doctor of Philosoph

Association of Manganese Biomarker Concentrations with Blood Pressure and Kidney Parameters among Healthy Adolescents: NHANES 2013–2018

Deficiency or excess exposure to manganese (Mn), an essential mineral, may have potentially adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. We hypothesized that Mn concentrations were associated with poorer blood pressure (BP) and kidney parameters such as estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and albumin creatinine ratio (ACR). We conducted a cross-sectional analysis of 1931 healthy U.S. adolescents aged 12–19 years participating in National Health and Nutrition Examination Survey cycles 2013–2014, 2015–2016, and 2017–2018. Blood and urine Mn concentrations were measured using inductively coupled plasma mass spectrometry. Systolic and diastolic BP were calculated as the average of available readings. eGFR was calculated from serum creatinine using the Bedside Schwartz equation. We performed multiple linear regression, adjusting for age, sex, body mass index, race/ethnicity, and poverty income ratio. We observed null relationships between blood Mn concentrations with eGFR, ACR, BUN, and BP. In a subset of 691 participants, we observed that a 10-fold increase in urine Mn was associated with a 16.4 mL/min higher eGFR (95% Confidence Interval: 11.1, 21.7). These exploratory findings should be interpreted cautiously and warrant investigation in longitudinal studies

Multiple arterial emboli secondary to left ventricular thrombus in a 35-year-old obese male

The very unusual case of a 35-year-old obese male patient with a left ventricular (LV) thrombus secondary to a silent myocardial infarction and resultant shower emboli to multiple arterial sites is described. His presentation with acute limb ischemia led to arterial imaging and the identification of the underlying cardiac pathology in addition to splenic and bilateral renal infarcts. He was also found to suffer from previously undiagnosed hypertension. He underwent femoral embolectomy and multiple arterial revascularization attempts but required bilateral above knee amputations and a prolonged intensive care unit stay. This rare and extreme example of a LV thrombus in a young male emphasizes the potential sequellae of the condition. Furthermore, with the increasing incidence of obesity this case demonstrates the importance of considering undiagnosed cardiovascular risk factors when assessing obese patients

The MOSDEF Survey: Mass, Metallicity, and Star-formation Rate at z~2.3

We present results on the z~2.3 mass-metallicity relation (MZR) using early observations from the MOSFIRE Deep Evolution Field (MOSDEF) survey. We use an initial sample of 87 star-forming galaxies with spectroscopic coverage of H\beta, [OIII]\lambda 5007, H\alpha, and [NII]\lambda 6584 rest-frame optical emission lines, and estimate the gas-phase oxygen abundance based on the N2 and O3N2 strong-line indicators. We find a positive correlation between stellar mass and metallicity among individual z~2.3 galaxies using both the N2 and O3N2 indicators. We also measure the emission-line ratios and corresponding oxygen abundances for composite spectra in bins of stellar mass. Among composite spectra, we find a monotonic increase in metallicity with increasing stellar mass, offset ~0.15-0.3 dex below the local MZR. When the sample is divided at the median star-formation rate (SFR), we do not observe significant SFR dependence of the z~2.3 MZR among either individual galaxies or composite spectra. We furthermore find that z~2.3 galaxies have metallicities ~0.1 dex lower at a given stellar mass and SFR than is observed locally. This offset suggests that high-redshift galaxies do not fall on the local "fundamental metallicity relation" among stellar mass, metallicity, and SFR, and may provide evidence of a phase of galaxy growth in which the gas reservoir is built up due to inflow rates that are higher than star-formation and outflow rates. However, robust conclusions regarding the gas-phase oxygen abundances of high-redshift galaxies await a systematic reappraisal of the application of locally calibrated metallicity indicators at high redshift.Comment: 12 pages, 6 figures, accepted for publication in the Astrophysical Journal (ApJ

The MOSDEF Survey: Detection of [OIII]λ\lambda4363 and the direct-method oxygen abundance of a star-forming galaxy at z=3.08

We present measurements of the electron-temperature based oxygen abundance for a highly star-forming galaxy at z=3.08, COSMOS-1908. This is the highest redshift at which [OIII]$\lambda$4363 has been detected, and the first time that this line has been measured at z>2. We estimate an oxygen abundance of 12+log(O/H)$=8.00^{+0.13}_{-0.14}$. This galaxy is a low-mass ($10^{9.3}$ M$_{\odot}$), highly star-forming ($\sim50$ M$_{\odot}$ yr$^{-1}$) system that hosts a young stellar population ($\sim160$ Myr). We investigate the physical conditions of the ionized gas in COSMOS-1908 and find that this galaxy has a high ionization parameter, little nebular reddening ($E(B-V)_{\rm gas}<0.14$), and a high electron density ($n_e\sim500$ cm$^{-3}$). We compare the ratios of strong oxygen, neon, and hydrogen lines to the direct-method oxygen abundance for COSMOS-1908 and additional star-forming galaxies at z=0-1.8 with [OIII]$\lambda$4363 measurements, and show that galaxies at z$\sim$1-3 follow the same strong-line correlations as galaxies in the local universe. This agreement suggests that the relationship between ionization parameter and O/H is similar for z$\sim$0 and high-redshift galaxies. These results imply that metallicity calibrations based on lines of oxygen, neon, and hydrogen do not strongly evolve with redshift and can reliably estimate abundances out to z$\sim$3, paving the way for robust measurements of the evolution of the mass-metallicity relation to high redshift.Comment: 7 pages, 3 figures, 1 table, accepted to ApJ Letter

The MOSDEF Survey: Electron Density and Ionization Parameter at z∼2.3z\sim2.3

Using observations from the MOSFIRE Deep Evolution Field (MOSDEF) survey, we investigate the physical conditions of star-forming regions in $z\sim2.3$ galaxies, specifically the electron density and ionization state. From measurements of the [O II]$\lambda\lambda$3726,3729 and [S II]$\lambda\lambda$6716,6731 doublets, we find a median electron density of $\sim250$ cm$^{-3}$ at $z\sim2.3$, an increase of an order of magnitude compared to measurements of galaxies at $z\sim0$. While $z\sim2.3$ galaxies are offset towards significantly higher O$_{32}$ values relative to local galaxies at fixed stellar mass, we find that the high-redshift sample follows a similar distribution to the low-metallicity tail of the local distribution in the O$_{32}$ vs. R$_{23}$ and O3N2 diagrams. Based on these results, we propose that $z\sim2.3$ star-forming galaxies have the same ionization parameter as local galaxies at fixed metallicity. In combination with simple photoionization models, the position of local and $z\sim2.3$ galaxies in excitation diagrams suggests that there is no significant change in the hardness of the ionizing spectrum at fixed metallicity from $z\sim0$ to $z\sim2.3$. We find that $z\sim2.3$ galaxies show no offset compared to low-metallicity local galaxies in emission line ratio diagrams involving only lines of hydrogen, oxygen, and sulfur, but show a systematic offset in diagrams involving [N II]$\lambda$6584. We conclude that the offset of $z\sim2.3$ galaxies from the local star-forming sequence in the [N II] BPT diagram is primarily driven by elevated N/O at fixed O/H compared to local galaxies. These results suggest that the local gas-phase and stellar metallicity sets the ionization state of star-forming regions at $z\sim0$ and $z\sim2$.Comment: 26 pages, 14 figures, accepted to Ap

The MOSDEF Survey: Excitation Properties of z∼2.3z\sim 2.3 Star-forming Galaxies

We present results on the excitation properties of z~2.3 galaxies using early observations from the MOSFIRE Deep Evolution Field (MOSDEF) Survey. With its coverage of the full suite of strong rest-frame optical emission lines, MOSDEF provides an unprecedented view of the rest-frame optical spectra of a representative sample of distant star-forming galaxies. We investigate the locations of z~2.3 MOSDEF galaxies in multiple emission-line diagnostic diagrams. These include the [OIII]/Hb vs. [NII]/Ha and [OIII]/Hb vs. [SII]/Ha "BPT" diagrams, as well as the O_32 vs. R_23 excitation diagram. We recover the well-known offset in the star-forming sequence of high-redshift galaxies in the [OIII]/Hb vs. [NII]/Ha BPT diagram relative to SDSS star-forming galaxies. However, the shift for our rest-frame optically selected sample is less significant than for rest-frame-UV selected and emission-line selected galaxies at z~2. Furthermore, we find that the offset is mass-dependent, only appearing within the low-mass half of the z~2.3 MOSDEF sample, where galaxies are shifted towards higher [NII]/Ha at fixed [OIII]/Hb. Within the [OIII]/Hb vs. [SII]/Ha and O_32 vs. R_23 diagrams, we find that z~2.3 galaxies are distributed like local ones, and therefore attribute the shift in the [OIII]/Hb vs. [NII]/Ha BPT diagram to elevated N/O abundance ratios among lower-mass (M_*<10^10 M_sun) high-redshift galaxies. The variation in N/O ratios calls into question the use at high redshift of oxygen abundance indicators based on nitrogen lines, but the apparent invariance with redshift of the excitation sequence in the O_32 vs. R_23 diagram paves the way for using the combination of O_32 and R_23 as an unbiased metallicity indicator over a wide range in redshift. This indicator will allow for an accurate characterization of the shape and normalization of the mass-metallicity relationship over more than 10 Gyr.Comment: 14 pages, 9 figures, accepted to Ap

CASE STUDIES OF ASYMMETRIES IN SWIMMING

An interrelated influence of strength, flexibility, anthropometric and technique asymmetries affects performance in swimming. Underpinning aetiologies include both acquired and inherited factors. The combination of factors varies among swimmers and therefore demands a multi-disciplinary case study approach to identify and correct asymmetries to improve performance and reduce incidence of injuries. The purpose of this presentation is to provide examples of analyses informing individualised interventions to correct asymmetries. Interventions comprise programmes of strength, flexibility, posture, and technique refinement. Analyses included measures of strength on the Biodex, measures of strength, posture, flexibility and anthropometry based on the International Society for the Advancement of Kinesiology (ISAK) conventions, and video-based qualitative and quantitative three-dimensional analysis of technique. Sample data of a breaststroke swimmer and a backstroke swimmer are presented to illustrate the interrelationships among strength, flexibility, posture, technique and performance