Life or Death? A Physiogenomic Approach to Understand Individual Variation in Responses to Hemorrhagic Shock

Severe hemorrhage due to trauma is a major cause of death throughout the world. It has often been observed that some victims are able to withstand hemorrhage better than others. For decades investigators have attempted to identify physiological mechanisms that distinguish survivors from nonsurvivors for the purpose of providing more informed therapies. As an alternative approach to address this issue, we have initiated a research program to identify genes and genetic mechanisms that contribute to this phenotype of survival time after controlled hemorrhage. From physiogenomic studies using inbred rat strains, we have demonstrated that this phenotype is a heritable quantitative trait, and is therefore a complex trait regulated by multiple genes. Our work continues to identify quantitative trait loci as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage. Our ultimate goal is to improve survival to traumatic hemorrhage and attendant shock via regulation of genetic mechanisms and to provide knowledge that will lead to genetically-informed personalized treatments

Resting sympathetic baroreflex sensitivity in subjects with low and high tolerance to central hypovolemia induced by lower body negative pressure

Central hypovolemia elicited by orthostasis or hemorrhage triggers sympathetically-mediated baroreflex responses to maintain organ perfusion; these reflexes are less sensitive in patients with orthostatic intolerance, and during conditions of severe blood loss, may result in cardiovascular collapse (decompensatory or circulatory shock). The ability to tolerate central hypovolemia is variable and physiological factors contributing to tolerance are emerging. We tested the hypothesis that resting muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (BRS) are attenuated in male and female subjects who have low tolerance (LT) to central hypovolemia induced by lower body negative pressure (LBNP). MSNA and diastolic arterial pressure (DAP) were recorded in 47 human subjects who subsequently underwent LBNP to tolerance (onset of presyncopal symptoms). LT subjects experienced presyncopal symptoms prior to completing LBNP of -60 mm Hg, and subjects with high tolerance (HT) experienced presyncopal symptoms after completing LBNP after -60 mmHg. Contrary to our hypothesis, resting MSNA burst incidence was not different between LT and HT subjects, and was not related to time to presyncope. BRS was assessed as the slope of the relationship between spontaneous fluctuations in DAP and MSNA during 5 min of supine rest. MSNA burst incidence/DAP correlations were greater than or equal to 0.5 in 37 subjects (LT: n= 9; HT: n=28), and BRS was not different between LT and HT (-1.8 ± 0.3 vs. -2.2 ± 0.2 bursts•(100 beats)-1•mmHg-1, p=0.29). We conclude that tolerance to central hypovolemia is not related to either resting MSNA or sympathetic BRS

Heart Rate Variability during Simulated Hemorrhage with Lower Body Negative Pressure in High and Low Tolerant Subjects

Heart rate variability (HRV) decreases during hemorrhage, and has been proposed as a new vital sign to assess cardiovascular stability in trauma patients. The purpose of this study was to determine if any of the HRV metrics could accurately distinguish between individuals with different tolerance to simulated hemorrhage. Specifically, we hypothesized that (1) HRV would be similar in low tolerant (LT) and high tolerant (HT) subjects at presyncope when both groups are on the verge of hemodynamic collapse; and (2) HRV could distinguish LT subjects at presyncope from hemodynamically stable HT subjects (i.e., at a submaximal level of hypovolemia). Lower body negative pressure (LBNP) was used as a model of hemorrhage in healthy human subjects, eliciting central hypovolemia to the point of presyncopal symptoms (onset of hemodynamic collapse). Subjects were classified as LT if presyncopal symptoms occurred during the −15 to −60 mmHg levels of LBNP, and HT if symptoms occurred after LBNP of −60 mmHg. A total of 20 HRV metrics were derived from R–R interval measurements at the time of presyncope, and at one level prior to presyncope (submax) in LT and HT groups. Only four HRV metrics (Long-range Detrended Fluctuation Analysis, Forbidden Words, Poincaré Plot Descriptor Ratio, and Fractal Dimensions by Curve Length) supported both hypotheses. These four HRV metrics were evaluated further for their ability to identify individual LT subjects at presyncope when compared to HT subjects at submax. Variability in individual LT and HT responses was so high that LT responses overlapped with HT responses by 85–97%. The sensitivity of these HRV metrics to distinguish between individual LT from HT subjects was 6–33%, and positive predictive values were 40–73%. These results indicate that while a small number of HRV metrics can accurately distinguish between LT and HT subjects using group mean data, individual HRV values are poor indicators of tolerance to hypovolemia

Sympathetic Responses to Central Hypovolemia: New Insights from Microneurographic Recordings

Hemorrhage remains a major cause of mortality following traumatic injury in both military and civilian settings. Lower body negative pressure (LBNP) has been used as an experimental model to study the compensatory phase of hemorrhage in conscious humans, as it elicits central hypovolemia like that induced by hemorrhage. One physiological compensatory mechanism that changes during the course of central hypovolemia induced by both LBNP and hemorrhage is a baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA), as assessed with microneurography. The purpose of this review is to describe recent results obtained using microneurography in our laboratory as well as those of others that have revealed new insights into mechanisms underlying compensatory increases in MSNA during progressive reductions in central blood volume and how MSNA is altered at the point of hemodynamic decompensation. We will also review recent work that has compared direct MSNA recordings with non-invasive surrogates of MSNA to determine the appropriateness of using such surrogates in assessing the clinical status of hemorrhaging patients

Mental Disorder in Children with Physical Conditions: a Pilot Study

OBJECTIVES: Methodologically, to assess the feasibility of participant recruitment and retention, as well as missing data in studying mental disorder among children newly diagnosed with chronic physical conditions (ie, multimorbidity). Substantively, to examine the prevalence of multimorbidity, identify sociodemographic correlates and model the influence of multimorbidity on changes in child quality of life and parental psychosocial outcomes over a 6-month follow-up. DESIGN: Prospective pilot study. SETTING: Two children\u27s tertiary-care hospitals. PARTICIPANTS: Children aged 6-16 years diagnosed in the past 6 months with one of the following: asthma, diabetes, epilepsy, food allergy or juvenile arthritis, and their parents. OUTCOME MEASURES: Response, participation and retention rates. Child mental disorder using the Mini International Neuropsychiatric Interview at baseline and 6 months. Child quality of life, parental symptoms of stress, anxiety and depression, and family functioning. All outcomes were parent reported. RESULTS: Response, participation and retention rates were 90%, 83% and 88%, respectively. Of the 50 children enrolled in the study, the prevalence of multimorbidity was 58% at baseline and 42% at 6 months. No sociodemographic characteristics were associated with multimorbidity. Multimorbidity at baseline was associated with declines over 6 months in the following quality of life domains: physical well-being, β=-4.82 (-8.47, -1.17); psychological well-being, β=-4.10 (-7.62, -0.58) and school environment, β=-4.17 (-8.18, -0.16). There was no association with parental psychosocial outcomes over time. CONCLUSIONS: Preliminary evidence suggests that mental disorder in children with a physical condition is very common and has a negative impact on quality of life over time. Based on the strong response rate and minimal attrition, our approach to study child multimorbidity appears feasible and suggests that multimorbidity is an important concern for families. Methodological and substantive findings from this pilot study have been used to implement a larger, more definitive study of child multimorbidity, which should lead to important clinical implications

Constraints on the Universal CIV Mass Density at z~6 from Early IR Spectra Obtained with the Magellan FIRE Spectrograph

We present a new determination of the intergalactic CIV mass density at 4.3 < z < 6.3. Our constraints are derived from high signal-to-noise spectra of seven quasars at z > 5.8 obtained with the newly commissioned FIRE spectrograph on the Magellan Baade telescope, coupled with six observations of northern objects taken from the literature. We confirm the presence of a downturn in the CIV abundance at =5.66 by a factor of 4.1 relative to its value at =4.96, as measured in the same sightlines. In the FIRE sample, a strong system previously reported in the literature as CIV at z=5.82 is re-identified as MgII at z=2.78, leading to a substantial downward revision in $\Omega_{CIV}$ for these prior studies. Additionally we confirm the presence of at least two systems with low-ionization CII, SiII, and OI absorption but relatively weak signal from CIV. The latter systems systems may be of interest if the downward trend in $\Omega_{CIV}$ at high redshift is driven in part by ionization effects.Comment: 14 pages, 6 figures, 2 tables. Submitted to Ap

The Last Eight-Billion Years of Intergalactic CIV Evolution

We surveyed the HST UV spectra of 49 low-redshift quasars for z < 1 CIV candidates, relying solely on the characteristic wavelength separation of the doublet. After consideration of the defining traits of CIV doublets (e.g., consistent line profiles, other associated transitions, etc.), we defined a sample of 38 definite (group G = 1) and five likely (G = 2) doublets with rest equivalent widths W_r for both lines detected at >= 3 sigma. We conducted Monte-Carlo completeness tests to measure the unblocked redshift (dz) and co-moving pathlength (dX) over which we were sensitive to CIV doublets of a range of equivalent widths and column densities. The absorber line density of (G = 1+2) doublets is dN/dX = 4.1+0.7/-0.6 for log N(C^+3) >= 13.2, and dN/dX has not evolved significantly since z = 5. The best-fit power-law to the G = 1 frequency distribution of column densities f(N(C^+3)) = k(N(C^+3)/N_0)^alpha_N has coefficient k = (0.67+0.18/-0.16) x 10^-14 cm^2 and exponent alpha_N = -1.50+0.17/-0.19, where N_0 = 10^14 cm^-2. Using the power-law model of f(N(C^+3)), we measured the C^+3 mass density relative to the critical density: Omega(C^+3) = (6.20+1.82/-1.52) x 10^-8 for 13 <= log N(C^+3) <= 15. This value is a 2.8+/-0.7 increase in Omega(C^+3) compared to the error-weighted mean from several 1 < z < 5 surveys for CIV absorbers. A simple linear regression to Omega(C^+3) over the age of the Universe indicates that Omega(C^+3) has slowly but steadily increased from z = 5 --> 0, with dOmega(C^+3)/dt_age = (0.42+/-0.2) x 10^-8 Gyr^-1.Comment: 61 pages; accepted by ApJ; includes changes based on referee repor

On the Kinematics of Cold, Metal-enriched Galactic Fountain Flows in Nearby Star-forming Galaxies

We use medium-resolution Keck/Echellette Spectrograph and Imager spectroscopy of bright quasars to study cool gas traced by CaII 3934,3969 and NaI 5891,5897 absorption in the interstellar/circumgalactic media of 21 foreground star-forming galaxies at redshifts 0.03 < z < 0.20 with stellar masses 7.4 < log M_*/M_sun < 10.6. The quasar-galaxy pairs were drawn from a unique sample of Sloan Digital Sky Survey quasar spectra with intervening nebular emission, and thus have exceptionally close impact parameters (R_perp < 13 kpc). The strength of this line emission implies that the galaxies' star formation rates (SFRs) span a broad range, with several lying well above the star-forming sequence. We use Voigt profile modeling to derive column densities and component velocities for each absorber, finding that column densities N(CaII) > 10^12.5 cm^-2 (N(NaI) > 10^12.0 cm^-2) occur with an incidence f_C(CaII) = 0.63^+0.10_-0.11 (f_C(NaI) = 0.57^+0.10_-0.11). We find no evidence for a dependence of f_C or the rest-frame equivalent widths W_r(CaII K) or W_r(NaI 5891) on R_perp or M_*. Instead, W_r(CaII K) is correlated with local SFR at >3sigma significance, suggesting that CaII traces star formation-driven outflows. While most of the absorbers have velocities within +/-50 km/s of the host redshift, their velocity widths (characterized by Delta v_90) are universally 30-177 km/s larger than that implied by tilted-ring modeling of the velocities of interstellar material. These kinematics must trace galactic fountain flows and demonstrate that they persist at R_perp > 5 kpc. Finally, we assess the relationship between dust reddening and W_r(CaII K) (W_r(NaI 5891)), finding that 33% (24%) of the absorbers are inconsistent with the best-fit Milky Way E(B-V)-W_r relations at >3sigma significance.Comment: 38 pages, 16 figures, 4 tables. Accepted to Ap

Three Year Aging of Prototype Flight Laser at 10 Khz and 1 Ns Pulses with External Frequency Doubler for the Icesat-2 Mission

We present the results of three year life-aging of a specially designed prototype flight source laser operating at 1064 nm, 10 kHz, 1ns, 15W average power and external frequency doubler. The Fibertek-designed, slightly pressurized air, enclosed-container source laser operated at 1064 nm in active Q-switching mode. The external frequency doubler was set in a clean room at a normal air pressure. The goal of the experiment was to measure degradation modes at 1064 and 532 nm discreetly. The external frequency doubler consisted of a Lithium triborate, LiB3O5, crystal operated at non-critical phase-matching. Due to 1064 nm diagnostic needs, the amount of fundamental frequency power available for doubling was 13.7W. The power generated at 532 nm was between 8.5W and 10W, depending on the level of stress and degradation. The life-aging consisted of double stress-step operation for doubler crystal, at 0.35 J/cm2 for almost 1 year, corresponding to normal conditions, and then at 0.93 J/cm2 for the rest of the experiment, corresponding to accelerated testing. We observed no degradation at the first step and linear degradation at the second step. The linear degradation at the second stress-step was related to doubler crystal output surface changes and linked to laser-assisted contamination. We discuss degradation model and estimate the expected lifetime for the flight laser at 532 nm. This work was done within the laser testing for NASA's Ice, Cloud, and land Elevation Satellite-2 (ICESat-2) LIDAR at Goddard Space Flight Center in Greenbelt, MD with the goal of 1 trillion shots lifetime

The Middle Way: East Asian masters students’ perceptions of critical argumentation in U.K. universities.

The paper explores the learning experiences of East Asian masters students in dealing with Western academic norms of critical thinking in classroom debate and assignment writing. The research takes a cultural approach, and employs grounded theory and case study methodology, the aims being for students to explain their perceptions of their personal learning journeys. The data suggest that the majority of students interviewed rejected full academic acculturation into Western norms of argumentation. They instead opted for a ‘Middle Way’ that synergizes the traditional cultural academic values held by many East Asian students with those elements of Western academic norms that are perceived to be aligned with these. This is a relatively new area of research which represents a challenge for British lecturers and students