Poor Cardiac Output Reserve in Pulmonary Arterial Hypertension is Associated With Right Ventricular Stiffness and Impaired Interventricular Dependence.

BACKGROUND: Pulmonary arterial hypertension is characterized by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (p-V) loop analysis to characterize the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS: RV p-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance, Eed) and ventricular interdependence (left ventricular transmural pressure, LVTMP) were compared at matched exercise stages. RESULTS: Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 ml·m-2, p=0.0001), with higher associated exercise afterload (Ea 1.76 versus 0.90 mmHg·mL-1, p<0.0001), RV stiffness (Eed 0.68 versus 0.26 mmHg·mL-1, p=0.003), and right-sided pressures (RA 14 versus 8 mmHg, p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2 mmHg, p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS: Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness, and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiologic PAH differences unapparent at rest.

A test of the frost wave hypothesis in a temperate ungulate.

Growing evidence supports the hypothesis that temperate herbivores surf the green wave of emerging plants during spring migration. Despite the importance of autumn migration, few studies have conceptualized resource tracking of temperate herbivores during this critical season. We adapted the frost wave hypothesis (FWH), which posits that animals pace their autumn migration to reduce exposure to snow but increase acquisition of forage. We tested the FWH in a population of mule deer in Wyoming, USA by tracking the autumn migrations of n = 163 mule deer that moved 15-288 km from summer to winter range. Migrating deer experienced similar amounts of snow but 1.4-2.1 times more residual forage than if they had naïve knowledge of when or how fast to migrate. Importantly, deer balanced exposure to snow and forage in a spatial manner. At the fine scale, deer avoided snow near their mountainous summer ranges and became more risk prone to snow near winter range. Aligning with their higher tolerance of snow and lingering behavior to acquire residual forage, deer increased stopover use by 1 ± 1 day (95% CI) day for every 10% of their migration completed. Our findings support the prediction that mule deer pace their autumn migration with the onset of snow and residual forage, but refine the FWH to include movement behavior en route that is spatially dynamic.

Occult right ventricular dysfunction and right ventricular-vascular uncoupling in left ventricular assist device recipients.

BACKGROUND: Detecting right heart failure post left ventricular assist device (LVAD) is challenging. Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction. METHODS: Thirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial coupling (ratio of Ees/Ea). RESULTS: LVAD patients had lower RV Ees (0.20 ± 0.08 vs 0.30 ± 0.15 mm Hg/ml, p = 0.01) and lower RV Ees/Ea (0.37 ± 0.14 vs 1.20 ± 0.54, p < 0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r = 0.68, p = 0.004) as well as the LVAD cohort itself (r = 0.78, p = 0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p = 0.048), driven by an inability to augment RV Ees (0.22 ± 0.11 vs 0.19 ± 0.02 mm Hg/ml, p = 0.95) to accommodate higher RV Ea (0.82 ± 0.38 vs 0.39 ± 0.08 mm Hg/ml, p = 0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients ((area under the curve) AUC = 0.80); during the ramp study, change in PAPi also correlated with change in RV Ees/Ea (r = 0.58, p = 0.04). CONCLUSIONS: LVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD left ventricular unloading, which reduces septal contractility.

Hidden Markov movement models reveal diverse seasonal movement patterns in two North American ungulates.

Animal movement is the mechanism connecting landscapes to fitness, and understanding variation in seasonal animal movements has benefited from the analysis and categorization of animal displacement. However, seasonal movement patterns can defy classification when movements are highly variable. Hidden Markov movement models (HMMs) are a class of latent-state models well-suited to modeling movement data. Here, we used HMMs to assess seasonal patterns of variation in the movement of pronghorn (Antilocapra americana), a species known for variable seasonal movements that challenge analytical approaches, while using a population of mule deer (Odocoileus hemionus), for whom seasonal movements are well-documented, as a comparison. We used population-level HMMs in a Bayesian framework to estimate a seasonal trend in the daily probability of transitioning between a short-distance local movement state and a long-distance movement state. The estimated seasonal patterns of movements in mule deer closely aligned with prior work based on indices of animal displacement: a short period of long-distance movements in the fall season and again in the spring, consistent with migrations to and from seasonal ranges. We found seasonal movement patterns for pronghorn were more variable, as a period of long-distance movements in the fall was followed by a winter period in which pronghorn were much more likely to further initiate and remain in a long-distance movement pattern compared with the movement patterns of mule deer. Overall, pronghorn were simply more likely to be in a long-distance movement pattern throughout the year. Hidden Markov movement models provide inference on seasonal movements similar to other methods, while providing a robust framework to understand movement patterns on shorter timescales and for more challenging movement patterns. Hidden Markov movement models can allow a rigorous assessment of the drivers of changes in movement patterns such as extreme weather events and land development, important for management and conservation.

Wherever I may roam-Human activity alters movements of red deer (Cervus elaphus) and elk (Cervus canadensis) across two continents.

Human activity and associated landscape modifications alter the movements of animals with consequences for populations and ecosystems worldwide. Species performing long-distance movements are thought to be particularly sensitive to human impact. Despite the increasing anthropogenic pressure, it remains challenging to understand and predict animals' responses to human activity. Here we address this knowledge gap using 1206 Global Positioning System movement trajectories of 815 individuals from 14 red deer (Cervus elaphus) and 14 elk (Cervus canadensis) populations spanning wide environmental gradients, namely the latitudinal range from the Alps to Scandinavia in Europe, and the Greater Yellowstone Ecosystem in North America. We measured individual-level movements relative to the environmental context, or movement expression, using the standardized metric Intensity of Use, reflecting both the directionality and extent of movements. We expected movement expression to be affected by resource (Normalized Difference Vegetation Index, NDVI) predictability and topography, but those factors to be superseded by human impact. Red deer and elk movement expression varied along a continuum, from highly segmented trajectories over relatively small areas (high intensity of use), to directed transitions through restricted corridors (low intensity of use). Human activity (Human Footprint Index, HFI) was the strongest driver of movement expression, with a steep increase in Intensity of Use as HFI increased, but only until a threshold was reached. After exceeding this level of impact, the Intensity of Use remained unchanged. These results indicate the overall sensitivity of Cervus movement expression to human activity and suggest a limitation of plastic responses under high human pressure, despite the species also occurring in human-dominated landscapes. Our work represents the first comparison of metric-based movement expression across widely distributed populations of a deer genus, contributing to the understanding and prediction of animals' responses to human activity.

Migrating mule deer compensate en route for phenological mismatches.

Billions of animals migrate to track seasonal pulses in resources. Optimally timing migration is a key strategy, yet the ability of animals to compensate for phenological mismatches en route is largely unknown. Using GPS movement data collected from 72 adult female deer over a 10-year duration, we study a population of mule deer (Odocoileus hemionus) in Wyoming that lack reliable cues on their desert winter range, causing them to start migration 70 days ahead to 52 days behind the wave of spring green-up. We show that individual deer arrive at their summer range within an average 6-day window by adjusting movement speed and stopover use. Late migrants move 2.5 times faster and spend 72% less time on stopovers than early migrants, which allows them to catch the green wave. Our findings suggest that ungulates, and potentially other migratory species, possess cognitive abilities to recognize where they are in space and time relative to key resources. Such behavioral capacity may allow migratory taxa to maintain foraging benefits amid rapidly changing phenology.

Metabolic profiling of in vivo right ventricular function and exercise performance in pulmonary arterial hypertension.

Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. Consecutive subjects with PAH (n = 23) underwent rest and exercise right heart catheterization with multibeat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared with N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurements for accuracy in modeling ventriculo-arterial parameters. Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched-chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed NT-proBNP in modeling RV contractility, diastolic function, and exercise performance. Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.NEW & NOTEWORTHY In this cohort of patients with pulmonary arterial hypertension (PAH), we investigate metabolomic associations with comprehensive right ventricular (RV) functional measurements derived from multibeat RV pressure-volume loop analysis. Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in the cardiopulmonary system's response to exercise stress. Metabolite profiles selected via unbiased analysis outperformed N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in predicting load-independent measures of RV function at rest and cardiopulmonary system performance under stress. Overall, this work suggests the potential for select metabolites to function as disease-specific biomarkers, offers insights into PAH pathobiology, and informs discovery of potentially targetable RV-centric pathways.

Case Report: When Two Is Worse Than One-Stereo Imbalance in a Case of Wavefront-guided Scleral Lenses.

SIGNIFICANCE: Wavefront-guided scleral lenses (WGSLs) reduce visually debilitating residual higher-order aberrations. Although reduced higher-order aberrations lead to improvement in monocular high-contrast visual acuity (VA), the success of the lenses in everyday life depends on additional factors such as retinal contrast, binocular balance, and stereoacuity. PURPOSE: This report describes a case where WGSLs provided improved monocular vision compared with scleral lenses (SLs) but reduced binocularity and stereoacuity. CASE REPORT: A 48-year-old woman with moderate keratoconus right eye (OD) and severe left eye (OS) was fitted with SLs and WGSLs. Visual acuity with best SLs was 20/20 -2 OD and 20/25 -2 OS. Residual higher-order root-mean-square (HORMS) wavefront error (6 mm pupil) was 0.56 µm OD and 1.38 µm OS. Visual acuity with WGSLs was 20/16 -2 OD and 20/25 +2 OS, and residual HORMS was 0.41 µm OD and 0.98 µm OS. Monocularly, WGSLs were reported to provide better VA. However, binocularly, the patient reported an "imbalanced feeling" and preferred the SLs over WGSLs. Binocular VA at distance was 20/25 with SLs and 20/25 -2 with WGSL. To investigate, the Worth Four-Dot test was performed, and the outcomes reported fusion with SLs but suppression OS at distance with WGSLs. Stereoacuity was 160 arc seconds at near and 120 arc seconds at distance with SLs and 400 arc seconds at near and >1200 arc seconds at distance with WGSLs. Dichoptic contrast balancing showed a balance point of 0.48 with SLs and 0.17 with WGSLs, indicating a strong preference toward OD. Simulation of the patient's retinal image revealed a greater difference in image contrast between the two eyes with WGSLs. CONCLUSIONS: Wavefront-guided scleral lenses reduced HORMS and improved VA compared with SLs. However, in this case, it inadvertently caused binocular imbalance. As WGSLs become more widely available, future work should include methods to optimize binocular balance to maximize overall patient satisfaction.

Wind-energy development alters pronghorn migration at multiple scales.

Migration is a critical behavioral strategy necessary for population persistence and ecosystem functioning, but migration routes have been increasingly disrupted by anthropogenic activities, including energy development. Wind energy is the world's fastest growing source of electricity and represents an important alternative to hydrocarbon extraction, but its effects on migratory species beyond birds and bats are not well understood. We evaluated the effects of wind-energy development on pronghorn migration, including behavior and habitat selection, to assess potential effects on connectivity and other functional benefits including stopovers. We monitored GPS-collared female pronghorn from 2010 to 2012 and 2018 to 2020 in south-central Wyoming, USA, an area with multiple wind-energy facilities in various stages of development and operation. Across all time periods, we collected 286 migration sequences from 117 individuals, including 121 spring migrations, 123 fall migrations, and 42 facultative winter migrations. While individuals continued to migrate through wind-energy facilities, pronghorn made important behavioral adjustments relative to turbines during migration. These included avoiding turbines when selecting stopover sites in spring and winter, selecting areas farther from turbines at a small scale in spring and winter, moving more quickly near turbines in spring (although pronghorn moved more slowly near turbines in the fall), and reducing fidelity to migration routes relative to wind turbines under construction in both spring and fall. For example, an increase in distance to turbine from 0 to 1 km translated to a 33% and 300% increase in the relative probability of selection for stopover sites in spring and winter, respectively. The behavioral adjustments pronghorn made relative to wind turbines could reduce the functional benefits of their migration, such as foraging success or the availability of specific routes, over the long term.

Industrial energy development decouples ungulate migration from the green wave.

The ability to freely move across the landscape to track the emergence of nutritious spring green-up (termed 'green-wave surfing') is key to the foraging strategy of migratory ungulates. Across the vast landscapes traversed by many migratory herds, habitats are being altered by development with unknown consequences for surfing. Using a unique long-term tracking dataset, we found that when energy development occurs within mule deer (Odocoileus hemionus) migration corridors, migrating animals become decoupled from the green wave. During the early phases of a coalbed natural gas development, deer synchronized their movements with peak green-up. But faced with increasing disturbance as development expanded, deer altered their movements by holding up at the edge of the gas field and letting the green wave pass them by. Development often modified only a small portion of the migration corridor but had far-reaching effects on behaviour before and after migrating deer encountered it, thus reducing surfing along the entire route by 38.65% over the 14-year study period. Our study suggests that industrial development within migratory corridors can change the behaviour of migrating ungulates and diminish the benefits of migration. Such disruptions to migratory behaviour present a common mechanism whereby corridors become unprofitable and could ultimately be lost on highly developed landscapes.

Body size and digestive system shape resource selection by ungulates: A cross-taxa test of the forage maturation hypothesis.

The forage maturation hypothesis (FMH) states that energy intake for ungulates is maximised when forage biomass is at intermediate levels. Nevertheless, metabolic allometry and different digestive systems suggest that resource selection should vary across ungulate species. By combining GPS relocations with remotely sensed data on forage characteristics and surface water, we quantified the effect of body size and digestive system in determining movements of 30 populations of hindgut fermenters (equids) and ruminants across biomes. Selection for intermediate forage biomass was negatively related to body size, regardless of digestive system. Selection for proximity to surface water was stronger for equids relative to ruminants, regardless of body size. To be more generalisable, we suggest that the FMH explicitly incorporate contingencies in body size and digestive system, with small-bodied ruminants selecting more strongly for potential energy intake, and hindgut fermenters selecting more strongly for surface water.

Migration distance and maternal resource allocation determine timing of birth in a large herbivore.

Birth timing is a key life-history characteristic that influences fitness and population performance. For migratory animals, however, appropriately timing birth on one seasonal range may be constrained by events occurring during other parts of the migratory cycle. We investigated how the use of capital and income resources may facilitate flexibility in reproductive phenology of migratory mule deer in western Wyoming, USA, over a 5-yr period (2015-2019). Specifically, we examined how seasonal interactions affected three interrelated life-history characteristics: fetal development, birth mass, and birth timing. Females in good nutritional condition at the onset of winter and those that migrated short distances had more developed fetuses (measured as fetal eye diameter in March). Variation in parturition date was explained largely by fetal development; however, there were up to 16 d of plasticity in expected birth date. Plasticity in expected birth date was shaped by income resources in the form of exposure to spring green-up. Although individuals that experienced greater exposure to spring green-up were able to advance expected birth date, being born early or late with respect to fetal development had no effect on birth mass of offspring. Furthermore, we investigated the trade-offs migrating mule deer face by evaluating support for existing theory that predicts that births should be matched to local peaks in resource availability at the birth site. In contrast to this prediction, only long-distance migrants that paced migration with the flush of spring green-up, giving birth shortly after ending migration, were able to match birth with spring green-up. Shorter-distance migrants completed migration sooner and gave birth earlier, seemingly trading off more time for offspring to grow and develop over greater access to resources. Thus, movement tactic had profound downstream effects on birth timing. These findings highlight a need to reconsider classical theory on optimal birth timing, which has focused solely on conditions at the birth site.

Life-history theory provides a framework for detecting resource limitation: a test of the Nutritional Buffer Hypothesis.

For ungulates and other long-lived species, life-history theory predicts that nutritional reserves are allocated to reproduction in a state-dependent manner because survival is highly conserved. Further, as per capita food abundance and nutritional reserves decline (i.e., density dependence intensifies), reproduction and recruitment become increasingly sensitive to weather. Thus, the degree to which weather influences vital rates should be associated with proximity to nutritional carrying capacity-a notion that we refer to as the Nutritional Buffer Hypothesis. We tested the Nutritional Buffer Hypothesis using six moose (Alces alces) populations that varied in calf recruitment (33-69 calves/100 cows). We predicted that populations with high calf recruitment were nutritionally buffered against the effects of unfavorable weather, and thus were below nutritional carrying capacity. We applied a suite of tools to quantify habitat and nutritional condition of each population and found that increased browse condition, forage quality, and body fat were associated with increased pregnancy and calf recruitment, thereby providing multiple lines of evidence that declines in calf recruitment were underpinned by resource limitation. From 2001 to 2015, recruitment was more sensitive to interannual variation in weather (e.g., winter severity, drought) and plant phenology (e.g., duration of spring) for populations with reduced browse condition, forage quality, and body fat, suggesting these populations lacked the nutritional reserves necessary to buffer demographic performance against the effects of unfavorable weather. Further, average within-population calf recruitment was determined by regional climatic variation, suggesting that the pattern of reduced recruitment near the southern range boundary of moose stems from an interaction between climate and resource limitation. When coupled with information on habitat, nutrition, weather, and climate, life-history theory provides a framework to estimate nutritional limitation, proximity to nutritional carrying capacity, and impacts of climate change for ungulates.

Drivers of site fidelity in ungulates.

While the tendency to return to previously visited locations-termed 'site fidelity'-is common in animals, the cause of this behaviour is not well understood. One hypothesis is that site fidelity is shaped by an animal's environment, such that animals living in landscapes with predictable resources have stronger site fidelity. Site fidelity may also be conditional on the success of animals' recent visits to that location, and it may become stronger with age as the animal accumulates experience in their landscape. Finally, differences between species, such as the way memory shapes site attractiveness, may interact with environmental drivers to modulate the strength of site fidelity. We compared inter-year site fidelity in 669 individuals across eight ungulate species fitted with GPS collars and occupying a range of environmental conditions in North America and Africa. We used a distance-based index of site fidelity and tested hypothesized drivers of site fidelity using linear mixed effects models, while accounting for variation in annual range size. Mule deer Odocoileus hemionus and moose Alces alces exhibited relatively strong site fidelity, while wildebeest Connochaetes taurinus and barren-ground caribou Rangifer tarandus granti had relatively weak fidelity. Site fidelity was strongest in predictable landscapes where vegetative greening occurred at regular intervals over time (i.e. high temporal contingency). Species differed in their response to spatial heterogeneity in greenness (i.e. spatial constancy). Site fidelity varied seasonally in some species, but remained constant over time in others. Elk employed a 'win-stay, lose-switch' strategy, in which successful resource tracking in the springtime resulted in strong site fidelity the following spring. Site fidelity did not vary with age in any species tested. Our results provide support for the environmental hypothesis, particularly that regularity in vegetative phenology shapes the strength of site fidelity at the inter-annual scale. Large unexplained differences in site fidelity suggest that other factors, possibly species-specific differences in attraction to known sites, contribute to variation in the expression of this behaviour. Understanding drivers of variation in site fidelity across groups of organisms living in different environments provides important behavioural context for predicting how animals will respond to environmental change.

Emerging Perspectives on Resource Tracking and Animal Movement Ecology.

Resource tracking, where animals increase energy gain by moving to track phenological variation in resources across space, is emerging as a fundamental attribute of animal movement ecology. However, a theoretical framework to understand when and where resource tracking should occur, and how resource tracking should lead to emergent ecological patterns, is lacking. We present a framework that unites concepts from optimal foraging theory and landscape ecology, which can be used to generate and test predictions on how resource dynamics shape animal movement across taxa, systems, and scales. Consideration of the interplay between animal movement and resource dynamics not only advances ecological understanding but can also guide biodiversity conservation in an era of global change.

Quantifying the Optical and Physical Consequences of Daily Cleaning on Conventional and Wavefront-guided Scleral Lenses.

SIGNIFICANCE: An equivalent 12 months of cleaning did not induce significant changes in the optical aberrations or base curves of scleral lenses. PURPOSE: This study aimed to test whether an equivalent of 12 months of manual cleaning alters the optical and physical properties of conventional and wavefront-guided scleral lenses. METHODS: Twelve scleral lenses (four repeats of three designs, termed A, B, and C) were manufactured in Boston XO material: design A, -5.00 D defocus; design B, -5.00 D defocus with -0.153-µm vertical coma; and design C, -5.00 D defocus with a full custom wavefront-guided correction (second to fifth Zernike radial orders) of an eye with severe keratoconus. One lens of each design group served as a control and was not cleaned. To simulate a year of cleaning, seven individuals cleaned nine lenses (three from each group) twice a day for 27 days using the palm technique and commercially available cleaners, resulting in 378 cleanings of each lens. Lens aberrations were optically profiled and base curve radii were measured at baseline and after every 42nd cleaning. Differences in higher-order root mean square (HORMS) wavefront error and base curve radii associated with cleaning were compared with clinical benchmarks and using sign tests. RESULTS: For the experimental lenses, median change in Seidel spherical dioptric power was +0.01 D (maximum, +0.025 D). Median change in HORMS wavefront error was 0.013 µm (maximum, 0.019 µm). All lenses exhibited HORMS changes less than one-eighth equivalent diopters (P = .002). Median percentage change in HORMS wavefront error in the three wavefront-guided lenses was 0.96% (maximum, 1.25%). Median change in base curve radii was 0.00 mm, with all lenses exhibiting changes (P = .002), less than the American National Standards Institute tolerance of 0.05 mm. CONCLUSIONS: Cleaning over an equivalent 12-month period did not induce clinically significant changes in the optical or base curve properties of conventional or wavefront-guided scleral lenses.