The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value.

Hippocampal activity represents many behaviorally important variables, including context, an animal's location within a given environmental context, time, and reward. Using longitudinal calcium imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature-the field propensity. Each cell's propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed-with many low, and some very high, propensity cells-and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell's propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.

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.

Cortical pattern generation during dexterous movement is input-driven.

The motor cortex controls skilled arm movement by sending temporal patterns of activity to lower motor centres1. Local cortical dynamics are thought to shape these patterns throughout movement execution2-4. External inputs have been implicated in setting the initial state of the motor cortex5,6, but they may also have a pattern-generating role. Here we dissect the contribution of local dynamics and inputs to cortical pattern generation during a prehension task in mice. Perturbing cortex to an aberrant state prevented movement initiation, but after the perturbation was released, cortex either bypassed the normal initial state and immediately generated the pattern that controls reaching or failed to generate this pattern. The difference in these two outcomes was probably a result of external inputs. We directly investigated the role of inputs by inactivating the thalamus; this perturbed cortical activity and disrupted limb kinematics at any stage of the movement. Activation of thalamocortical axon terminals at different frequencies disrupted cortical activity and arm movement in a graded manner. Simultaneous recordings revealed that both thalamic activity and the current state of cortex predicted changes in cortical activity. Thus, the pattern generator for dexterous arm movement is distributed across multiple, strongly interacting brain regions.

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.

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.

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.

Understanding how temperature shifts could impact infectious disease.

Climate change is expected to have complex effects on infectious diseases, causing some to increase, others to decrease, and many to shift their distributions. There have been several important advances in understanding the role of climate and climate change on wildlife and human infectious disease dynamics over the past several years. This essay examines 3 major areas of advancement, which include improvements to mechanistic disease models, investigations into the importance of climate variability to disease dynamics, and understanding the consequences of thermal mismatches between host and parasites. Applying the new information derived from these advances to climate-disease models and addressing the pressing knowledge gaps that we identify should improve the capacity to predict how climate change will affect disease risk for both wildlife and humans.

Long-term costs and cost-effectiveness of adjunctive corticosteroids for patients with septic shock in New Zealand.

OBJECTIVE: The aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. DESIGN: This is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. SETTING: The study was conducted in New Zealand. PARTICIPANTS AND INTERVENTION: Patients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. MAIN OUTCOME MEASURES: Healthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. RESULTS: Of 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. CONCLUSIONS: In New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.

Blood flow restriction in the presence or absence of muscle contractions does not preserve vasculature structure and function following 14-days of limb immobilization.

PURPOSE: Limb immobilization causes local vasculature to experience detrimental adaptations. Simple strategies to increase blood flow (heating, fidgeting) successfully prevent acute (≤ 1 day) impairments; however, none have leveraged the hyperemic response over prolonged periods (weeks) mirroring injury rehabilitation. Throughout a 14-day unilateral limb immobilization, we sought to preserve vascular structure and responsiveness by repeatedly activating a reactive hyperemic response via blood flow restriction (BFR) and amplifying this stimulus by combining BFR with electric muscle stimulation (EMS). METHODS: Young healthy adults (M:F = 14:17, age = 22.4 ± 3.7 years) were randomly assigned to control, BFR, or BFR + EMS groups. BFR and BFR + EMS groups were treated for 30 min twice daily (3 × 10 min ischemia-reperfusion cycles; 15% maximal voluntary contraction EMS), 5 days/week (20 total sessions). Before and after immobilization, artery diameter, flow-mediated dilation (FMD) and blood flow measures were collected in the superficial femoral artery (SFA). RESULTS: Following immobilization, there was less retrograde blood velocity (+ 1.8 ± 3.6 cm s-1, P = 0.01), but not retrograde shear (P = 0.097). All groups displayed reduced baseline and peak SFA diameter following immobilization (- 0.46 ± 0.41 mm and - 0.43 ± 0.39 mm, P < 0.01); however, there were no differences by group or across time for FMD (% diameter change, shear-corrected, or allometrically scaled) nor microvascular function assessed by peak flow capacity. CONCLUSION: Following immobilization, our results reveal (1) neither BFR nor BFR + EMS mitigate artery structure impairments, (2) intervention-induced shear stress did not affect vascular function assessed by FMD, and (3) retrograde blood velocity is reduced at rest offering potential insight to mechanisms of flow regulation. In conclusion, BFR appears insufficient as a treatment strategy for preventing macrovascular dysfunction during limb immobilization.

The Effect of Body Position on Measures of Arterial Stiffness in Humans.

BACKGROUND: The dynamics ofpulsatile waveforms travelling the central aorta are governed by pressures and arterial compliance. Arterial stiffness, the inverse of compliance, is an independent risk factor for cardiovascular disease and has been suggested as a superior risk index compared to brachial blood pressure (BP). Arterial stiffness is typically measured via carotid-femoral pulse wave velocity (cfPWV) in the supine position; however, different body positions alter orthostatic column height, impacting heart rate and BP. The purpose of this investigation was to examine different body positions and associated measures of cfPWV. METHODS: Measures of resting cfPWV were acquired simultaneously with BP during supine, head-up tilt (HUT), head-down tilt (HDT), and Fowler's position, all at 45 degrees from vertical. RESULTS: Relative to supine, cfPWV was increased 1.1 ± 1.0 and 1.5 ± 1.1 m/s (both p ≤ 0.001) in HUT and Fowler's positions, respectively. Supine to HDT cfPWV was unaltered (p = 0.1), despite an increase in mean arterial pressure (MAP) (10 ± 9 mm Hg). When cfPWV was normalized to MAP, the same effects persisted (p ≤ 0.001). CONCLUSION: Increasing orthostatic column height by changing posture independently increases resting cfPWV, concurrent with increases in BP. This data demonstrates the impact of body position on measures of central artery stiffness, which may have clinical relevance.

Avian responses to extreme weather across functional traits and temporal scales.

Extreme weather, including heat waves, droughts, and high rainfall, is becoming more common and affecting a diversity of species and taxa. However, researchers lack a framework that can anticipate how diverse species will respond to weather extremes spanning weeks to months. Here we used high-resolution occurrence data from eBird, a global citizen science initiative, and dynamic species distribution models to examine how 109 North American bird species ranging in migration distance, diet, body size, habitat preference, and prevalence (commonness) respond to extreme heat, drought, and rainfall across a wide range of temporal scales. Across species, temperature influenced species' distributions more than precipitation at weekly and monthly scales, while precipitation was more important at seasonal scales. Phylogenetically controlled multivariate models revealed that migration distance was the most important factor mediating responses to extremely hot or dry weeks; residents and short-distance migrants occurred less often following extreme heat. At monthly or seasonal scales, less common birds experienced decreases in occurrence following drought-like conditions, while widespread species were unaffected. Spatial predictions demonstrated variation in responses to extreme weather across species' ranges, with predicted decreases in occurrence up to 40% in parts of ranges. Our results highlight that extreme weather has variable and potentially strong implications for birds at different time scales, but these responses are mediated by life-history characteristics. As weather once considered extreme occurs more frequently, researchers and managers require a better understanding of how diverse species respond to extreme conditions.

Mineralocorticoid Dysfunction during Critical Illness: A Review of the Evidence.

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.

Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

The influence of obesity on coagulation in healthy term pregnancy as assessed by rotational thromboelastometry.

BACKGROUND: Rotational thromboelastometry (ROTEM® ) is a point-of-care coagulation test which has been used to demonstrate hypercoagulability in pregnant populations and obese populations. AIM: The aim of this study was to assess the combined effect of pregnancy and obesity on coagulation using ROTEM® in healthy pregnant women of varying body mass indices (BMIs) presenting for elective caesarean delivery. MATERIALS AND METHODS: Ethics approval was granted for recruitment of women presenting for elective caesarean delivery. Women with any condition affecting coagulation were excluded. The ROTEM® parameters of extrinsically activated thromboelastometric test / fibrin polymerisation test (EXTEM/FIBTEM) amplitude at five minutes (A5), coagulation time (CT), maximum clot firmness (MCF) and clot formation time (CFT) were compared between three different groups: normal weight, overweight and obese women. RESULTS: One hundred and eighty-five women presenting for elective caesarean delivery met inclusion criteria and were divided into three groups; normal weight (BMI < 25 kg/m2 , n = 86), overweight (BMI 25-29.9 kg/m2 , n = 54) and obese (BMI ≥ 30 kg/m2 , n = 45). They had a mean (SD) age of 32.7 ± 5.0 years and the median (interquartile range) BMI of 21.9 kg/m2 (20.5-23.0), 27.0 kg/m2 (26.0-28.5), 36.0 kg/m2 (32.2-41.8) for the normal weight, overweight and obese groups respectively. Forty-one (22.2%) women were nulliparous. Across the three groups for FIBTEM A5 (P = 0.018), FIBTEM MCF (P = 0.032), FIBTEM CFT (P = 0.047) and EXTEM MCF (P = 0.015) there was evidence of increasing coagulability with increasing BMI. However, following Bonferroni correction, this was no longer significant. CONCLUSIONS: There is no association between BMI and ROTEM® parameters in pregnant women presenting for elective caesarean delivery at term.

Impacts of thermal mismatches on chytrid fungus Batrachochytrium dendrobatidis prevalence are moderated by life stage, body size, elevation and latitude.

Global climate change is increasing the frequency of unpredictable weather conditions; however, it remains unclear how species-level and geographic factors, including body size and latitude, moderate impacts of unusually warm or cool temperatures on disease. Because larger and lower-latitude hosts generally have slower acclimation times than smaller and higher-latitude hosts, we hypothesised that their disease susceptibility increases under 'thermal mismatches' or differences between baseline climate and the temperature during surveying for disease. Here, we examined how thermal mismatches interact with body size, life stage, habitat, latitude, elevation, phylogeny and International Union for Conservation of Nature (IUCN) conservation status to predict infection prevalence of the chytrid fungus Batrachochytrium dendrobatidis (Bd) in a global analysis of 32 291 amphibian hosts. As hypothesised, we found that the susceptibility of larger hosts and hosts from lower latitudes to Bd was influenced by thermal mismatches. Furthermore, hosts of conservation concern were more susceptible than others following thermal mismatches, suggesting that thermal mismatches might have contributed to recent amphibian declines.

An interaction between climate change and infectious disease drove widespread amphibian declines.

Climate change might drive species declines by altering species interactions, such as host-parasite interactions. However, few studies have combined experiments, field data, and historical climate records to provide evidence that an interaction between climate change and disease caused any host declines. A recently proposed hypothesis, the thermal mismatch hypothesis, could identify host species that are vulnerable to disease under climate change because it predicts that cool- and warm-adapted hosts should be vulnerable to disease at unusually warm and cool temperatures, respectively. Here, we conduct experiments on Atelopus zeteki, a critically endangered, captively bred frog that prefers relatively cool temperatures, and show that frogs have high pathogen loads and high mortality rates only when exposed to a combination of the pathogenic chytrid fungus (Batrachochytrium dendrobatidis) and high temperatures, as predicted by the thermal mismatch hypothesis. Further, we tested various hypotheses to explain recent declines experienced by species in the amphibian genus Atelopus that are thought to be associated with B. dendrobatidis and reveal that these declines are best explained by the thermal mismatch hypothesis. As in our experiments, only the combination of rapid increases in temperature and infectious disease could account for the patterns of declines, especially in species adapted to relatively cool environments. After combining experiments on declining hosts with spatiotemporal patterns in the field, our findings are consistent with the hypothesis that widespread species declines, including possible extinctions, have been driven by an interaction between increasing temperatures and infectious disease. Moreover, our findings suggest that hosts adapted to relatively cool conditions will be most vulnerable to the combination of increases in mean temperature and emerging infectious diseases.

Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model.

BACKGROUND: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. METHODS: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. RESULTS: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P < 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P < 0.001). CONCLUSIONS: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.

Hydrocortisone Compared with Placebo in Patients with Septic Shock Satisfying the Sepsis-3 Diagnostic Criteria and APROCCHSS Study Inclusion Criteria: A Post Hoc Analysis of the ADRENAL Trial.

BACKGROUND: Two recent randomized controlled trials (Adjunctive Glucocorticoid Therapy in Patients with Septic Shock [ADRENAL] and Activated Protein C and Corticosteroids for Human Septic Shock [APROCCHSS]) of corticosteroids in patients with septic shock reported different treatment effects on 90-day mortality. Both trials enrolled patients who met the criteria for septic shock using the second international consensus definitions for sepsis and septic shock (Sepsis-2), but the APROCCHSS trial mandated a greater severity of shock as an inclusion criterion. METHODS: The authors conducted post hoc sensitivity analyses of the ADRENAL trial to determine the effects of hydrocortisone versus placebo in subgroups selected using third international consensus definitions for sepsis and septic shock (Sepsis-3) diagnostic criteria or APROCCHSS inclusion criteria. RESULTS: There were 1,950 subjects (973 hydrocortisone and 977 placebo) who met the Sepsis-3 criteria (ADRENAL-Sepsis-3 cohort) and 905 patients (455 hydrocortisone and 450 placebo) who met the APROCCHSS criteria (ADRENAL-APROCCHSS cohort). At 90 days after randomization, in the ADRENAL-Sepsis-3 cohort, 312 of 963 (32.4%) and 337 of 958 (35.2%) patients assigned to hydrocortisone and placebo, respectively, had died (odds ratio, 0.86; 95% CI, 0.70 to 1.06; P = 0.166). The corresponding figures for the ADRENAL-APROCCHSS cohorts were 187 of 453 (41.3%) and 200 of 445 (44.9%), respectively (odds ratio, 0.84; 95% CI, 0.60 to 1.17; P = 0.303). There was no statistically significant difference in the time to death between the groups during the 90 days after randomization (hazard ratio = 0.87; 95% CI, 0.75 to 1.02; P = 0.082 for ADRENAL-Sepsis-3; and hazard ratio = 0.86; 95% CI, 0.71 to 1.06; P = 0.156 for ADRENAL-APROCCHSS cohorts). In both cohorts, patients assigned to hydrocortisone had faster resolution of shock. In the ADRENAL-Sepsis-3 cohort, patients assigned to hydrocortisone had an increase in the number of days alive and free of mechanical ventilation (57.0 ± 37.2 vs. 53.7 ± 38.2 days; 95% CI, 0.40 to 7.04; P = 0.028) and the number of days alive and free of the intensive care unit (54.3 ± 36.0 vs. 51.0 ± 37.1; 95% CI, 0.82 to 7.24; P = 0.014). CONCLUSIONS: In a post hoc analysis of the ADRENAL trial participants who fulfilled either the Sepsis-3 or the APROCCHSS inclusion criteria, a continuous infusion of hydrocortisone did not result in a lower 90-day mortality than placebo in septic shock.