Are novel or locally adapted pathogens more devastating and why? Resolving opposing hypotheses.

There is a rich literature highlighting that pathogens are generally better adapted to infect local than novel hosts, and a separate seemingly contradictory literature indicating that novel pathogens pose the greatest threat to biodiversity and public health. Here, using Batrachochytrium dendrobatidis, the fungus associated with worldwide amphibian declines, we test the hypothesis that there is enough variance in "novel" (quantified by geographic and phylogenetic distance) host-pathogen outcomes to pose substantial risk of pathogen introductions despite local adaptation being common. Our continental-scale common garden experiment and global-scale meta-analysis demonstrate that local amphibian-fungal interactions result in higher pathogen prevalence, pathogen growth, and host mortality, but novel interactions led to variable consequences with especially virulent host-pathogen combinations still occurring. Thus, while most pathogen introductions are benign, enough variance exists in novel host-pathogen outcomes that moving organisms around the planet greatly increases the chance of pathogen introductions causing profound harm.

A meta-analysis on global change drivers and the risk of infectious disease.

Anthropogenic change is contributing to the rise in emerging infectious diseases, which are significantly correlated with socioeconomic, environmental and ecological factors1. Studies have shown that infectious disease risk is modified by changes to biodiversity2-6, climate change7-11, chemical pollution12-14, landscape transformations15-20 and species introductions21. However, it remains unclear which global change drivers most increase disease and under what contexts. Here we amassed a dataset from the literature that contains 2,938 observations of infectious disease responses to global change drivers across 1,497 host-parasite combinations, including plant, animal and human hosts. We found that biodiversity loss, chemical pollution, climate change and introduced species are associated with increases in disease-related end points or harm, whereas urbanization is associated with decreases in disease end points. Natural biodiversity gradients, deforestation and forest fragmentation are comparatively unimportant or idiosyncratic as drivers of disease. Overall, these results are consistent across human and non-human diseases. Nevertheless, context-dependent effects of the global change drivers on disease were found to be common. The findings uncovered by this meta-analysis should help target disease management and surveillance efforts towards global change drivers that increase disease. Specifically, reducing greenhouse gas emissions, managing ecosystem health, and preventing biological invasions and biodiversity loss could help to reduce the burden of plant, animal and human diseases, especially when coupled with improvements to social and economic determinants of health.

Specific connectivity optimizes learning in thalamocortical loops.

Thalamocortical loops have a central role in cognition and motor control, but precisely how they contribute to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for the thalamus in shaping cortical dynamics through learning. Since signals undergo a compression from the cortex to the thalamus, we hypothesized that the computational role of the thalamus depends critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic projections specialized to communicate an efference copy of the cortical output benefit motor control, while communicating the modes of highest variance is optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination tasks and found corticothalamic communication consistent with these predictions. These results suggest that the thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.

A Genome-Wide Association Study of Serum Metabolite Profiles in Septic Shock Patients.

OBJECTIVES: We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology. DESIGN: Retrospective multicenter cohort studies of septic shock patients. SETTING: All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion. PATIENTS: Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10-8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity). CONCLUSIONS: We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.

A priori free spectral unmixing with periodic absorbance changes: application for auto-calibrated intraoperative functional brain mapping.

Spectral unmixing designates techniques that allow to decompose measured spectra into linear or non-linear combination of spectra of all targets (endmembers). This technique was initially developed for satellite applications, but it is now also widely used in biomedical applications. However, several drawbacks limit the use of these techniques with standard optical devices like RGB cameras. The devices need to be calibrated and a a priori on the observed scene is often necessary. We propose a new method for estimating endmembers and their proportion automatically and without calibration of the acquisition device based on near separable non-negative matrix factorization. This method estimates the endmembers on spectra of absorbance changes presenting periodic events. This is very common in in vivo biomedical and medical optical imaging where hemodynamics dominate the absorbance fluctuations. We applied the method for identifying functional brain areas during neurosurgery using four different RGB cameras (an industrial camera, a smartphone and two surgical microscopes). Results obtained with the auto-calibration method were consistent with the intraoperative gold standards. Endmembers estimated with the auto-calibration method were similar to the calibrated endmembers used in the modified Beer-Lambert law. The similarity was particularly strong when both cardiac and respiratory periodic events were considered. This work can allow a widespread use of spectral imaging in the industrial or medical field.

EARLY PERSISTENT LYMPHOPENIA AND RISK OF DEATH IN CRITICALLY ILL PATIENTS WITH AND WITHOUT SEPSIS.

ABSTRACT: Purpose: To examine the relationship of early persistent lymphopenia with hospital survival in critically ill patients with and without sepsis to assess whether it can be considered a treatable trait. Methods: Retrospective database analysis of patients with nonelective admission to intensive care units (ICUs) during January 2015 to December 2018. Patients were classified as having sepsis if the Acute Physiology and Chronic Health Evaluation III admission diagnostic code included sepsis or coded for an infection combined with a Sequential Organ Failure Assessment score of ≥2. We defined early persistent lymphopenia at two thresholds (absolute lymphocyte count [ALC] <1.0 and <0.75 × 10 9 /L) based on two qualifying values recorded during the first 4 days in ICU. The main outcome measure was time to in-hospital death. Results: Of 8,507 eligible patients, 7,605 (89.4%) had two ALCs recorded during their first 4 days in ICU; of these, 1,482 (19.5%) had sepsis. Persistent lymphopenia (ALC <1.0) was present in 728 of 1,482 (49.1%) and 2,302 of 6,123 (37.6%) patients with and without sepsis, respectively. For ALC <0.75, the results were 487 of 1,482 (32.9%) and 1,125 of 6,123 (18.4%), respectively. Of 3,030 patients with persistent lymphopenia (ALC <1.0), 562 (18.5%) died compared with 439 of 4,575 (9.6%) without persistent lymphopenia. Persistent lymphopenia was an independent risk factor for in-hospital death in all patients. The hazard ratios for death at ALC <1.0 were 1.89 (95% confidence interval, 1.32-2.71; P = 0.0005) and 1.17 (95% confidence interval, 1.02-1.35; P = 0.0246) in patients with and without sepsis respectively. Conclusions: Early persistent lymphopenia is common in critically ill patients and associated with increased risk of death in patients with and without sepsis. Although the association is stronger in patients with sepsis, lymphopenia is a candidate to be considered a treatable trait; drugs that reverse lymphopenia should be trialed in critically ill patients.

Spatial and seasonal variation in thermal sensitivity within North American bird species.

Responses of wildlife to climate change are typically quantified at the species level, but physiological evidence suggests significant intraspecific variation in thermal sensitivity given adaptation to local environments and plasticity required to adjust to seasonal environments. Spatial and temporal variation in thermal responses may carry important implications for climate change vulnerability; for instance, sensitivity to extreme weather may increase in specific regions or seasons. Here, we leverage high-resolution observational data from eBird to understand regional and seasonal variation in thermal sensitivity for 21 bird species. Across their ranges, most birds demonstrated regional and seasonal variation in both thermal peak and range, or the temperature and range of temperatures when observations peaked. Some birds demonstrated constant thermal peaks or ranges across their geographical distributions, while others varied according to local and current environmental conditions. Across species, birds typically demonstrated either geographical or seasonal adaptation to climate. Local adaptation and phenotypic plasticity are likely important but neglected aspects of organismal responses to climate change.

Supporting evidence for an "arterial pump" venous return mechanism in humans.

Blood flow in large veins is dependent on arterial-atrial pressure gradients and pumping mechanisms in concert with valve recruitment. Classic descriptions of muscle and respiratory pumps describe venous transmural pressure changes that cause flow. Not often considered is the transmission of pulsatile energy from arteries to veins directly adjacent to each other. Recently, an ex vivo study demonstrated a novel arterial pump effect in venoarterial bundles when valves were active in managing venous flow. We sought to show in vivo evidence of this arterial pump mechanism in 16 healthy young adults. Venous blood flow was measured in the venoarterial bundled deep femoral vein (DFV) and the greater saphenous vein (GSV), which is not bundled with an artery. Veins were studied through randomized body positions of -6° head-down tilt (HDT), supine, 20° head-up tilt (HUT), and 40° HUT, with the assumption that greater HUT postures increased valve dependence to observe the arterial pump effect. Between 20° and 40° HUT conditions, bundled DFV blood flow did not change (68 ± 36 vs. 71 ± 56 mL·min-1; Padj > 0.99), whereas nonbundled GSV blood flow decreased (6.1 ± 4.8 vs. 3.5 ± 3.9 mL·min-1; P = 0.01). Diameters between 20° and 40° HUT conditions increased in DFV (0.90 ± 0.16 vs. 1.04 ± 0.19 cm; P < 0.01), but not in GSV (0.33 ± 0.10 vs. 0.32 ± 0.08 cm; P = 0.60). These data support previous ex vivo observations that when venous pressure gradients rely on valve recruitment, presence of an adjacent artery may protect against further decreases in blood flow. The arterial pump mechanism is an underappreciated contributor to venous return and warrants further investigation.NEW & NOTEWORTHY Venous return mechanisms have classically considered muscle and respiratory pumps; however, recent ex vivo evidence suggests that pulsatile energy imparted from arteries to adjacent bundled veins can increase venous flow under certain driving pressures. We tested this concept in humans by manipulating hydrostatic pressures and measuring flow in bundled and nonbundled veins. The bundled vein exhibited flow preservation at the highest hydrostatic pressure. We suggest a novel conservation of energy mechanism within the circulatory system.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Blood Pressure Management Goals in Critically Ill Aneurysmal Subarachnoid Hemorrhage Patients in Australia and New Zealand.

INTRODUCTION: Blood pressure (BP) management is common in patients with aneurysmal subarachnoid hemorrhage (SAH) admitted to an intensive care unit. However, the practice patterns of BP management (timing, dose, and duration) have not been studied locally. METHODS: This post hoc analysis explored BP management goals (defined as the setting of a minimum systolic BP target or application of induced hypertension) in patients enrolled into the PROMOTE-SAH study in eleven neurosurgical centers in Australia and New Zealand. The primary outcome was 'dead or disabled' (modified Rankin Score ≥4) at 6 months, with the hypothesis being that setting BP management goals would be associated with improved outcomes. RESULTS: BP management goals were recorded in 266 of 357 (75%) patients, of which 149 were recorded as receiving induced hypertension for delayed cerebral ischemia (DCI) or vasospasm on 738 (19%) study days. In patients with a minimum systolic BP goal recorded (on 2067 d), the indication for the BP management goal was vasospasm or DCI on 651 (32%) days; no indication for BP management goals was documented on 1416 (69%) days. Crude analysis demonstrated an association between setting BP management goals and reduced death or disability (P=0.03), but this association was not significant after adjustment for the presence of DCI or vasospasm and clustered by the site. CONCLUSIONS: BP management goals are commonly 'prescribed' to aSAH patients admitted to an intensive care unit in Australia and New Zealand, but BP management goal setting was not associated with improved outcomes in the adjusted analysis.

Time Management Strategies of Rock Climbers in World Cup Bouldering Finals.

Competitive rock climbing recently made its Olympic debut, but minimal published research exists regarding training and competition strategies. Time management strategies define the structured approach climbers take in bouldering competitions to successfully obtain a "top" or a "zone" hold. During finals rounds of the International Federation of Sport Climbing bouldering competitions, climbers are allotted 240 s to complete a boulder. Variables influencing a climber's time management strategies include their work-to-rest intervals, and the frequency of their attempts or rests. Video analysis of International Federation of Sport Climbing competitions was used to collect time management strategy data of professional climbers. Fifty-six boulders (28 female and 28 male boulders) over the 2019 International Federation of Sport Climbing season were analyzed. Time management strategies variables were compared between slab/slab-like and non-slab bouldering styles using generalized estimating equations with significance set to p < 0.05. Additionally, we determined trends in success rates for various styles of boulders. There were no differences in the number of attempts taken per boulder between slab/slab-like and non-slab boulders (3.7 ± 2.3 and 3.8 ± 2.4, p = 0.97), but climbers spent more time actively climbing on slab/slab-like (92 ± 36 s) compared to non-slab boulders (65 ± 26 s, p < 0.001). Trends in the success rate suggest climbers who take more than 6 attempts on any boulder style are unsuccessful. The results of this study provide practical information that can be used by coaches and athletes to guide training and competition strategy.

Heating-induced peripheral limb microvascular vasodilation reduces arterial wave reflection.

Arterial wave reflection augments cardiac afterload increasing myocardial demands. Mathematical models and comparative physiology suggest that the lower limbs are the primary source of reflected waves; however, in vivo human evidence corroborating these observations is lacking. This study was designed to determine whether the vasculature of the lower or upper limbs contributes more to wave reflection. We hypothesized that lower limb heating will result in larger reductions in central wave reflection compared with upper limb heating due to local vasodilation of a larger microvascular bed. Fifteen healthy adults (8 females, 24 ± 3.6 yr) completed a within-subjects experimental crossover protocol with a washout period. The right upper and lower limbs were heated in a randomized order using 38°C water-perfused tubing with a 30-min break between protocols. Central wave reflection was calculated using pressure-flow relationships derived from aortic blood flow and carotid arterial pressure at baseline and after 30 min of heating. We observed a main effect of time for reflected wave amplitude (12.8 ± 2.7 to 12.2 ± 2.6 mmHg; P = 0.03) and augmentation index (-7.5 ± 8.9% to -4.5 ± 9.1%; P = 0.03). No significant main effects or interactions were noted for forward wave amplitude, reflected wave arrival time, or central relative wave reflection magnitude (all P values >0.23). Unilateral limb heating reduced reflected wave amplitude; however, the lack of a difference between conditions does not support the hypothesis that the lower limbs are the primary source of reflection. Future investigations should consider alternative vascular beds, such as splanchnic circulation.NEW & NOTEWORTHY Lower limb contributions to central wave reflections have been theorized without direct evidence in humans. In this study, mild passive heating was used to locally vasodilate either the right arm or leg to control local wave reflection sites. Heating in general reduced the reflected wave amplitude, but there were no differences between the arm or leg heating intervention, failing to provide support for the lower limbs as a primary contributor to wave reflection in humans.

Investigating sensor location on the effectiveness of continuous glucose monitoring during exercise in a non-diabetic population.

The purpose of this investigation was to evaluate whether continuous glucose monitoring (CGM) sensors worn on the active muscle may provide enhanced insight into glucose control in non-diabetic participants during cycling exercise compared to traditional sensor placement on the arm. Data from 9 healthy participants (F:3) was recorded using CGM sensors on the arm (triceps brachii) and leg (vastus medialis) following 100 g glucose ingestion during 30 min experimental visits of: resting control, graded cycling, electrically stimulated quadriceps contractions, and passive whole-body heating. Finger capillary glucose was used to assess sensor accuracy. Under control conditions, the traditional arm sensor better reflected capillary glucose, with a mean absolute relative difference (MARD) of 12.4 ± 9.3% versus 18.3 ± 11.4% in the leg (P = 0.02). For the intended use during exercise, the sensor-site difference was attenuated, with similar MARDs during cycling (arm:15.5 ± 12% versus leg:16.7 ± 10.8%, P = 0.96) and quadriceps stimulation (arm:15.5 ± 14.8% versus leg:13.9 ± 9.5%, P = 0.9). At rest, glucose at the leg was consistently lower than the arm (P = 0.01); whereas, during graded cycling, the leg-glucose was lower only after maximal intensity exercise (P = 0.02). There was no difference between sensors during quadriceps stimulation (P = 0.8). Passive heating caused leg-skin temperature to increase by 3.1 ± 1.8°C versus 1.1 ± 0.72°C at the arm (P = 0.002), elevating MARD in the leg (23.5 ± 16.2%) and lowering glucose in the leg (P < 0.001). At rest, traditional placement of CGM sensors on the arm may best reflect blood glucose; however, during cycling, placement on the leg may offer greater insight to working muscle glucose concentrations, and this is likely due to greater blood-flow rather than muscle contractions.HighlightsWearing a continuous glucose monitoring (CGM) sensor on the arm may better reflect capillary glucose concentrations compared to wearing a sensor on the inner thigh at rest.With passive or active leg-muscle contractions, site-specific differences compared to capillary samples are attenuated; therefore, wearing a CGM sensor on the active-muscle during exercise may provide greater information to non-diabetic athletes regarding glucose flux at the active muscle.Discrepancies in CGM sensors worn at different sites likely primarily reflects differences in blood flow, as passive skin heating caused the largest magnitude difference between arm and leg sensor readings compared to the other experimental conditions (control, electric muscle stimulation, and cycling exercise).

An emergent temporal basis set robustly supports cerebellar time-series learning.

The cerebellum is considered a "learning machine" essential for time interval estimation underlying motor coordination and other behaviors. Theoretical work has proposed that the cerebellum's input recipient structure, the granule cell layer (GCL), performs pattern separation of inputs that facilitates learning in Purkinje cells (P-cells). However, the relationship between input reformatting and learning has remained debated, with roles emphasized for pattern separation features from sparsification to decorrelation. We took a novel approach by training a minimalist model of the cerebellar cortex to learn complex time-series data from time-varying inputs, typical during movements. The model robustly produced temporal basis sets from these inputs, and the resultant GCL output supported better learning of temporally complex target functions than mossy fibers alone. Learning was optimized at intermediate threshold levels, supporting relatively dense granule cell activity, yet the key statistical features in GCL population activity that drove learning differed from those seen previously for classification tasks. These findings advance testable hypotheses for mechanisms of temporal basis set formation and predict that moderately dense population activity optimizes learning.NEW & NOTEWORTHY During movement, mossy fiber inputs to the cerebellum relay time-varying information with strong intrinsic relationships to ongoing movement. Are such mossy fibers signals sufficient to support Purkinje signals and learning? In a model, we show how the GCL greatly improves Purkinje learning of complex, temporally dynamic signals relative to mossy fibers alone. Learning-optimized GCL population activity was moderately dense, which retained intrinsic input variance while also performing pattern separation.

Daily activity timing in the Anthropocene.

Animals are facing novel 'timescapes' in which the stimuli entraining their daily activity patterns no longer match historical conditions due to anthropogenic disturbance. However, the ecological effects (e.g., altered physiology, species interactions) of novel activity timing are virtually unknown. We reviewed 1328 studies and found relatively few focusing on anthropogenic effects on activity timing. We suggest three hypotheses to stimulate future research: (i) activity-timing mismatches determine ecological effects, (ii) duration and timing of timescape modification influence effects, and (iii) consequences of altered activity timing vary biogeographically due to broad-scale variation in factors compressing timescapes. The continued growth of sampling technologies promises to facilitate the study of the consequences of altered activity timing, with emerging applications for biodiversity conservation.

Patient-Level Meta-Analysis of Low-Dose Hydrocortisone in Adults with Septic Shock.

Low-Dose Hydrocortisone and Septic ShockCorticosteroids have been evaluated as a therapy for septic shock for more than 50 years. However, uncertainty persists about their effects on mortality. Pirracchio and colleagues undertake a patient-level meta-analysis to answer this important question.

A multicentre observational study of the use of antiseizure medication in patients with aneurysmal subarachnoid haemorrhage in the PROMOTE-SAH study.

Our objective was to describe antiseizure medication (ASM) prescription patterns, and associations between ASM use and death and disability outcomes in patients with aneurysmal subarachnoid haemorrhage (aSAH) admitted to ICU. This was a multi-centre prospective observational study. The study took place in eleven ICUs across Australia and New Zealand. Data was collected from 1 April 2017 to 1 October 2018. Three hundred and fifty-seven adult patients with aSAH were enrolled. The primary outcome was to describe patterns of ASM prescription. The secondary outcome of interest was death or disability (modified Rankin Scale (mRS) score ≥ 4) at six months, and its association with ASM therapy, and relevant clinical subgroups. Forty percent of patients received an ASM and the most commonly used agent was levetiracetam. The median length of ASM administration was eight days (IQR 4.5-12.5). A number of patients with prehospital seizures did not receive ASM therapy (14/55, 2725%). There was a tendency towards ASM prescription with both higher radiological and clinical grade aSAH. There was no significant association between death or disability at six month (mRS ≥ 4) and ASM vs No ASM prescription. Testing for an interaction effect between ASM administration and WFNS grade suggested inferior outcomes with ASM use in lower aSAH grades (p = 0.04). In conclusion, the prescription of ASM for aSAH in Australia is variable across and within sites, with the majority of patients not receiving ASM chemoprophylaxis. We demonstrated no significant association between death or disability at six months and the use of ASM. There may be an association with poorer outcomes in patients with lower grade aSAH. This finding requires further exploration.

Network-medicine framework for studying disease trajectories in U.S. veterans.

A better understanding of the sequential and temporal aspects in which diseases occur in patient's lives is essential for developing improved intervention strategies that reduce burden and increase the quality of health services. Here we present a network-based framework to study disease relationships using Electronic Health Records from > 9 million patients in the United States Veterans Health Administration (VHA) system. We create the Temporal Disease Network, which maps the sequential aspects of disease co-occurrence among patients and demonstrate that network properties reflect clinical aspects of the respective diseases. We use the Temporal Disease Network to identify disease groups that reflect patterns of disease co-occurrence and the flow of patients among diagnoses. Finally, we define a strategy for the identification of trajectories that lead from one disease to another. The framework presented here has the potential to offer new insights for disease treatment and prevention in large health care systems.

Correction: Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models.

[This corrects the article DOI: 10.1371/journal.pntd.0005568.].