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Importance: Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head.Objective: To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis.Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021.Study Selection: Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate.Data Extraction and Synthesis: Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021.Main Outcomes and Measures: Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS).Results: Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, -2.1; 95% CrI, -4.1 to -0.3; high certainty), baricitinib, 4 mg daily (MD, -3.2; 95% CrI, -5.7 to -0.8; high certainty), baricitinib, 2 mg daily (MD, -5.2; 95% CrI, -7.5 to -2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, -3.5; 95% CrI, -5.8 to -1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, -1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS.Conclusions and Relevance: In this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores.

An individual’s fitness cost associated with environmental change likely depends on the rate of adaptive phenotypic plasticity, and yet our understanding of plasticity rates in an ecological and evolutionary context remains limited. We provide the first quantitative synthesis of existing plasticity rate data, focusing on acclimation of temperature tolerance in ectothermic animals, where we demonstrate applicability of a recently proposed analytical approach. The analyses reveal considerable variation in plasticity rates of this trait among species, with half-times (how long it takes for the initial deviation from the acclimated phenotype to be reduced by 50% when individuals are shifted to a new environment) ranging from 3.7 to 770.2 h. Furthermore, rates differ among higher taxa, being higher for amphibians and reptiles than for crustaceans and fishes, and with insects being intermediate. We argue that a more comprehensive understanding of phenotypic plasticity will be attained through increased focus on the rate parameter.

Invasive predatory species are frequently observed to cause evolutionary responses in prey phenotypes, which in turn may lead to evolutionary shifts in the population dynamics of prey. Research has provided a link between rates of predation and the evolution of prey population growth in the lab, but studies from natural populations are rare. Here, we tested for evolutionary changes in population dynamics parameters of zooplankton Daphnia pulicaria following invasion by the predator Bythotrephes longimanus into Lake Kegonsa, Wisconsin, US. We used a resurrection ecological approach, whereby clones from pre- and post-invasive periods were hatched from eggs obtained in sediment cores and were used in a 3-month growth experiment. Based on these data, we estimated intrinsic population growth rates (r), the shape of density dependence (θ) and carrying capacities (K) using theta-logistic models. We found that post-invasion Daphnia maintained a higher r and K under these controlled, predation-free laboratory conditions. Evidence for changes in θ was weaker. Whereas previous experimental evolution studies of predator–prey interactions have demonstrated that genotypes that have evolved under predation have inferior competitive ability when the predator is absent, this was not the case for the Daphnia. Given that our study was conducted in a laboratory environment and the possibility for genotype-by-environment interactions, extrapolating these apparent counterintuitive results to the wild should be done with caution. However, barring such complications, we discuss how selection for reduced predator exposure, either temporally or spatially, may have led to the observed changes. This scenario suggests that complexities in ecological interactions represents a challenge when predicting the evolutionary responses of population dynamics to changes in predation pressure in natural systems.

An individual’s fitness cost associated with environmental change depends on the rate of adaptive phenotypic plasticity, and yet our understanding of plasticity rates in an ecological and evolutionary context remains limited. We provide the first quantitative synthesis of existing plasticity rate data, focusing on acclimation of temperature tolerance in ectothermic animals, where we demonstrate applicability of a recently proposed analytical approach. The analyses reveal considerable variation in plasticity rates of this trait among species, with half-times (how long it takes for the initial deviation from the acclimated phenotype to be reduced by 50% when individuals are shifted to a new environment) ranging from 3.7 to 770.2 h. Furthermore, rates differ among higher taxa, being higher for amphibians and reptiles than for crustaceans and fishes, and with insects being intermediate. We argue that a more comprehensive understanding of phenotypic plasticity will be attained through increased focus on the rate parameter.

Life history theory predicts that investment per offspring should correlate negatively with the\ud quality of environment offspring are anticipated to encounter; parents may use their own\ud experience as juveniles to predict this environment and may modulate offspring traits such as\ud growth capacity as well as initial size. We manipulated nutrient levels in the juvenile habitat of\ud wild Atlantic salmon Salmo salar to investigate the hypothesis that the egg size maximizing\ud juvenile growth and survival depends on environmental quality. We also tested whether\ud offspring traits were related to parental growth trajectory. Mothers that grew fast when young\ud produced more, smaller offspring than mothers that had grown slowly to reach the same size.\ud Despite their size disadvantage, offspring of faster-growing mothers grew faster than those of\ud slow-growing mothers in all environments, counter to the expectation that they would be\ud competitively disadvantaged. However, they had lower relative survival in environments where\ud the density of older predatory/competitor fish was relatively high. These links between maternal\ud (but not paternal) growth trajectory and offspring survival rate were independent of egg size,\ud underscoring that mothers may be adjusting egg traits other than size to suit the anticipated\ud environment faced by their offspring.

BACKGROUND: Limited data are available on the effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis (AD).OBJECTIVE: To investigate COVID-19 outcomes in patients with AD treated with or without systemic immunomodulatory treatments, using a global registry platform.METHODS: Clinicians were encouraged to report cases of COVID-19 in their patients with AD in the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Atopic Dermatitis (SECURE-AD) registry. Data entered from 1 April 2020 to 31 October 2021 were analysed using multivariable logistic regression. The primary outcome was hospitalization from COVID-19, according to AD treatment groups.RESULTS: 442 AD patients (mean age 35.9 years, 51.8% male) from 27 countries with strongly suspected or confirmed COVID-19 were included in analyses. 428 (96.8%) patients were treated with a single systemic therapy (n = 297 [67.2%]) or topical therapy only (n = 131 [29.6%]). Most patients treated with systemic therapies received dupilumab (n = 216). Fourteen patients (3.2%) received a combination of systemic therapies. Twenty-six patients (5.9%) were hospitalized. No deaths were reported. Patients treated with topical treatments had significantly higher odds of hospitalization, compared with those treated with dupilumab monotherapy (odds ratio (OR) 4.65 [95%CI 1.71-14.78]), including after adjustment for confounding variables (adjusted OR (aOR) 4.99 [95%CI 1.4-20.84]). Combination systemic therapy which did not include systemic corticosteroids was associated with increased odds of hospitalization, compared with single agent non-steroidal immunosuppressive systemic treatment (OR 8.09 [95%CI 0.4-59.96], aOR 37.57 [95%CI 1.05-871.11]). Hospitalization was most likely in patients treated with combination systemic therapy which included systemic corticosteroids (OR 40.43 [95%CI 8.16-207.49], aOR 45.75 [95%CI 4.54-616.22]).CONCLUSIONS: Overall, the risk of COVID-19 complications appears low in patients with AD, even when treated with systemic immunomodulatory agents. Dupilumab monotherapy was associated with lower hospitalization than other therapies. Combination systemic treatment, particularly combinations including systemic corticosteroids, was associated with the highest risk of severe COVID-19.

Metabolic rate is a trait that may evolve in response to the direct and indirect effects of predator-induced mortality. Predators may indirectly alter selection by lowering prey densities and increasing resource availability or by intensifying resource limitation through changes in prey behavior (e.g., use of less productive areas). In the current study, we quantify the evolution of metabolic rate in the zooplankton

With rapid and less predictable environmental change emerging as the ‘new norm’, understanding how individuals tolerate environmental stress via plastic, often reversible changes to the phenotype (i.e., reversible phenotypic plasticity, RPP), remains a key issue in ecology. Here, we examine the potential for better understanding how organisms overcome environmental challenges within their own lifetimes by scrutinizing a somewhat overlooked aspect of RPP, namely the rate at which it can occur. Although recent advances in the field provide indication of the aspects of environmental change where RPP rates may be of particular ecological relevance, we observe that current theoretical models do not consider the evolutionary potential of the rate of RPP. Whilst recent theory underscores the importance of environmental predictability in determining the slope of the evolved reaction norm for a given trait (i.e., how much plasticity can occur), a hitherto neglected possibility is that the rate of plasticity might be a more dynamic component of this relationship than previously assumed. If the rate of plasticity itself can evolve, as empirical evidence foreshadows, rates of plasticity may have the potential to alter the level predictability in the environment as perceived by the organism and thus influence the slope of the evolved reaction norm. However, optimality in the rate of phenotypic plasticity, its evolutionary dynamics in different environments and influence of constraints imposed by associated costs remain unexplored and may represent fruitful avenues of exploration in future theoretical and empirical treatments of the topic. We conclude by reviewing published studies of RPP rates, providing suggestions for improving the measurement of RPP rates, both in terms of experimental design and in the statistical quantification of this component of plasticity. acclimation, acclimation rate, acclimation time-course, phenotypic plasticity, plasticity rate, rapid environmental change, timescale of plasticity

Despite considerable theoretical interest in how the evolution of phenotypic plasticity should be shaped by environmental variability and stochasticity, how individuals actually respond to these aspects of the environment within their own lifetimes remains unclear. We propose that this understanding has been hampered by experimental approaches that expose organisms to fluctuating environments (typically treatments where fluctuations in the environment are cyclical vs. erratic) for a pre‐determined duration while ensuring that the mean environment over that the entire exposure period is invariable. This approach implicitly assumes that responses to the mean and variance/predictability in the environment occur over the same time‐scale. If this assumption is false, one potential outcome is that phenotypic differences among the treatment groups might arise in response to differences in the mean environment that are present over shorter time periods among those same treatment groups. We illustrate an experimental design that (a) creates variation in the level of environmental predictability, (b) allows for estimation of the time‐scale over which the phenotypic response to the mean environment occurs and (c) permits statistical estimation of the effect of predictability in the environmental variable of interest while controlling for any effect of the mean environment over the relevant temporal scale. Using the clonally reproducing zooplankton species Daphnia magna, we test for within‐generation plasticity in the ability to tolerate high temperature following exposure to multiple temperature treatments with the same overall mean, but where the pattern of fluctuations differed among them. This approach revealed that heat tolerance in Daphnia was not influenced by variability in temperature per se nor the predictability of fluctuations in temperature but adjusted in response to the mean temperature they experienced 24 hr prior to measurement. Our results suggest that conclusions arising from studies that employ a single manipulation of environmental predictability and which cannot consider such potentially confounding effects may be premature. A free Plain Language Summary can be found within the Supporting Information of this article.

Using data from wild Atlantic salmon Salmo salar returning to spawn in seven Scottish rivers, we developed a model of fecundity based on individual body size and key developmental traits. We used a novel approach to model selection which maximises predictive accuracy for application to target river stocks to select the best from a suite of Bayesian hierarchical models. This approach aims to ensure the optimal model within the candidate set includes covariates that best predict out-of-sample data to estimate fecundity in areas where no direct observations are available. In addition to body size, the final model included the developmental characteristics of age at smolting and years spent at sea. Using two independent long-term monitoring datasets, the consequences of ignoring these characteristics was revealed by comparing predictions from the best model with models that omitted them.

Background A rapid expansion of systemic immunological treatment options for atopic dermatitis (AD) has created a need for clinically relevant and understandable comparative efficacy and safety information for patients and clinicians. Given the scarcity of head-to-head trials, network meta-analysis (NMA) is an alternative way to enable robust comparisons among treatment options; however, NMA results are often complex and difficult to directly implement in shared decision-making. Objective The aim of this study is to develop a website that effectively presents the results of a living systematic review and NMA on AD treatments to patient and clinician users. Methods We conducted a multimethod study using iterative feedback from adults with AD, adult caregivers of children with AD, dermatologists, and allergists within a user-centered design framework. We used questionnaires followed by workshops among patients and clinicians to develop and improve the website interface. Usability testing was done with a caregiver of a patient with eczema. Results Questionnaires were completed by 31 adults with AD or caregivers and 94 clinicians. Patients and caregivers felt it was very important to know about new treatments (20/31, 65%). Clinicians felt the lack of evidence-based comparisons between treatments was a barrier to care (55/93, 59%). “Avoiding dangerous side effects” was ranked as the most important priority for patients (weighted ranking 5.2/7, with higher ranking being more important), and “improving patients’ overall symptoms” was the most important priority for clinicians (weighted ranking 5.0/6). A total of 4 patients and 7 clinicians participated in workshops; they appreciated visualizations of the NMA results and found the website valuable for comparing different treatments. The patients suggested changes to simplify the interface and clarify terminology related to comparative efficacy. The user in the usability testing found the website intuitive to navigate. Conclusions We developed a website, “eczematherapies.com,” with a user-centered design approach. Visualizations of NMA results enable users to compare treatments as part of their shared decision-making process.

Purpose of review Refinement in machine learning (ML) techniques and approaches has rapidly expanded artificial intelligence applications for the diagnosis and classification of heart failure (HF). This review is designed to provide the clinician with the basics of ML, as well as this technologies future utility in HF diagnosis and the potential impact on patient outcomes. Recent findings Recent studies applying ML methods to unique data sets available from electrocardiography, vectorcardiography, echocardiography, and electronic health records show significant promise for improving diagnosis, enhancing detection, and advancing treatment of HF. Innovations in both supervised and unsupervised methods have heightened the diagnostic accuracy of models developed to identify the presence of HF and further augmentation of model capabilities are likely utilizing ensembles of ML algorithms derived from different techniques. Summary This article is an overview of recent applications of ML to achieve improved diagnosis of HF and the resultant implications for patient management.

Widespread declines in the body size of aquatic ectotherms have been attributed to the poorer ability of older, larger individuals to tolerate high temperature. Here, using the thermal death time curve framework, we investigate the relationship between temperature tolerance and size/age by measuring the change in heat tolerance of the keystone zooplankton species Daphnia magna across a range of temperature intensities (and hence exposures of varying duration) among individuals that differed up to 3-fold in size and thus varied in age also. Across the gradient of exposure temperatures, younger, smaller individuals were more tolerant than older, larger individuals. This suggests that the young and the small may be better equipped to withstand temperature challenges that are both intense/brief and more moderate/prolonged. Our study generalizes results obtained from more acute tolerance assays, providing physiological evidence consistent with the observed reductions in ectotherm body size as a response to warming in aquatic systems.

When a change in the environment occurs, organisms can maintain an optimal phenotypic state via plastic, reversible changes to their phenotypes. These adjustments, when occurring within a generation, are described as the process of acclimation. While acclimation has been studied for more than half a century, global environmental change has stimulated renewed interest in quantifying variation in the rate and capacity with which this process occurs, particularly among ectothermic organisms. Yet, despite the likely ecological importance of acclimation capacity and rate, how these traits change throughout life among members of the same species is largely unstudied. Here we investigate these relationships by measuring the acute heat tolerance of the clonally reproducing zooplankter Daphnia magna of different size/age and acclimation status. The heat tolerance of individuals completely acclimated to relatively warm (28°C) or cool (17°C) temperatures diverged during development, indicating that older, larger individuals had a greater capacity to increase heat tolerance. However, when cool acclimated individuals were briefly exposed to the warm temperature (i.e. were ‘heat-hardened'), it was younger, smaller animals with less capacity to acclimate that were able to do so more rapidly because they obtained or came closer to obtaining complete acclimation of heat tolerance. Our results illustrate that within a species, individuals can differ substantially in how rapidly and by how much they can respond to environmental change. We urge greater investigation of the intraspecific relationship between acclimation and development along with further consideration of the factors that might contribute to these enigmatic patterns of phenotypic variation.

The concept of self-defense in international law has been subject to discussion in recent years particularly in relation to its application on the fight against terrorism. The article re-considers such an application in the light of customary international law and via the use of the case of Afghanistan. More specifically the article aims at demonstrating how the Afghanistan mission informed the development of the classical concept of self-defense in the context of international security assistance. Via a historical presentation of the use of the concept of self-defense the work reveals key developments in the field.

Three sludge types (primary sludge, secondary sludge, and anaerobic digested sludge) and centrate produced from a local municipal wastewater treatment plant were treated by the microwave enhanced advanced oxidation process. All sludge types exhibited a certain degree of solids solubilization and phosphorus release, as well as altered physical properties after the treatment. The extent of treatment was influenced by the inherent characteristics of sludge itself, besides the treatment process conditions, such as temperature and hydrogen peroxide dosage. The microwave enhanced advanced oxidation process was very effective for the treatment of all types of sludge for purpose of solids solubilisation, and nutrients release for resource recovery. Very high soluble chemical oxygen demand concentrations (62%) and total suspended solids reduction (75%) were obtained in the treated secondary sludge conducted in the pilot-scale continuous-flow system. The microwave enhanced advanced oxidation treatment system shall be used for treating both primary and secondary sludge, and therefore, the system shall be installed in the treatment train after an aerobic biological treatment system, and before an anaerobic digestion system to gain the maximum process efficiency.

This study investigated the effectiveness of bench and pilot-scale microwave enhanced advanced oxidation process (MW-AOP) for treatment of sewage sludge in neutral, acidic (pH 4) and alkaline (pH 9) conditions. The MW-AOP treatments were very effective: total suspended solids reduction and chemical oxygen demand solubilization were better in the sets at pH 9 than at pH 4. Alkaline conditions would be more favorable for the subsequent anaerobic digestion for biogas production. Release of orthophosphate, particle size distribution, dewatering properties and settling of the sets at pH 4 were better than at pH 9. The supernatants obtained from the sets at pH 4 had a high orthophosphate concentration and a low total suspended solids content, which were more suitable for struvite (a fertilizer) recovery process. Energy consumption was lower for the pH adjusted treatment sets compared to those of MW only and MW-AOP at neutral conditions; energy for the pH adjusted sets varied between 0.32 and 0.41 kWh/L of sludge treated. The results indicated that the MW-AOP could reduce the volume of sludge for disposal, and produce a high quality treated effluent suitable for further resource and energy recovery. Depending on the needs of each wastewater treatment plant’s treatment priority, the experimental conditions applied in the process can be adjusted accordingly.

Background and Objective Coronary artery disease (CAD) and heart failure are the most common cardiovascular diseases. Non-invasive diagnostic testing for CAD requires radiation, heart rate acceleration, and imaging infrastructure. Early detection of left ventricular dysfunction is critical in heart failure management, the best measure of which is an elevated left ventricular end-diastolic pressure (LVEDP) that can only be measured using invasive cardiac catheterization. There exists a need for non-invasive, safe, and fast diagnostic testing for CAD and elevated LVEDP. This research employs nonlinear dynamics to assess for significant CAD and elevated LVEDP using non-invasively acquired photoplethysmographic (PPG) and three-dimensional orthogonal voltage gradient (OVG) signals. PPG (variations of the blood volume perfusing the tissue) and OVG (mechano-electrical activity of the heart) signals represent the dynamics of the cardiovascular system. Methods PPG and OVG were simultaneously acquired from two cohorts, (i) symptomatic subjects that underwent invasive cardiac catheterization, the gold standard test (408 CAD positive with stenosis≥ 70% and 186 with LVEDP≥ 20 mmHg) and (ii) asymptomatic healthy controls (676). A set of Poincare-based synchrony features were developed to characterize the interactions between the OVG and PPG signals. The extracted features were employed to train machine learning models for CAD and LVEDP. Five-fold cross-validation was used and the best model was selected based on the average area under the receiver operating characteristic curve (AUC) across 100 runs, then assessed using a hold-out test set. Results The Elastic Net model developed on the synchrony features can effectively classify CAD positive subjects from healthy controls with an average validation AUC=0.90±0.03 and an AUC= 0.89 on the test set. The developed model for LVEDP can discriminate subjects with elevated LVEDP from healthy controls with an average validation AUC=0.89±0.03 and an AUC=0.89 on the test set. The feature contributions results showed that the selection of a proper registration point for Poincare analysis is essential for the development of predictive models for different disease targets. Conclusions Nonlinear features from simultaneously-acquired signals used as inputs to machine learning can assess CAD and LVEDP safely and accurately with an easy-to-use, portable device, utilized at the point-of-care without radiation, contrast, or patient preparation.

When a change in the environment occurs, organisms can maintain an optimal phenotypic state via plastic, reversible changes to their phenotypes. These adjustments, when occurring within a generation, are described as the process of acclimation. While acclimation has been studied for more than half a century, global environmental change has stimulated renewed interest in quantifying variation in the rate and capacity with which this process occurs, particularly among ectothermic organisms. Yet, despite the likely ecological importance of acclimation capacity and rate, how these traits change throughout life among members of the same species is largely unstudied. Here we investigate these relationships by measuring the acute heat tolerance of the clonally reproducing zooplankter Daphnia magna of different size/age and acclimation status. The heat tolerance of individuals completely acclimated to relatively warm (28°C) or cool (17°C) temperatures diverged during development, indicating that older, larger individuals had a greater capacity to increase heat tolerance. However, when cool acclimated individuals were briefly exposed to the warm temperature (i.e. were ‘heat-hardened'), it was younger, smaller animals with less capacity to acclimate that were able to do so more rapidly because they obtained or came closer to obtaining complete acclimation of heat tolerance. Our results illustrate that within a species, individuals can differ substantially in how rapidly and by how much they can respond to environmental change. We urge greater investigation of the intraspecific relationship between acclimation and development along with further consideration of the factors that might contribute to these enigmatic patterns of phenotypic variation.

The capacity of organisms to acclimate will influence their ability to cope with ongoing global changes in thermal regimes. Here we highlight methodological issues associated with recent attempts to quantify variation in acclimation capacity among taxa and environments, and describe how these may introduce bias to conclusions. We then propose a measure of thermal acclimation capacity that more directly quantifies the process of acclimation. Future studies of variation in acclimation capacity should critically evaluate whether their chosen empirical metric accurately reflects the theoretical concept of acclimation.

A shift from coral to macroalgae dominance of reef systems affected by volcanically acidified waters around Maug (Mariana Islands, North Pacific Ocean) increases fears that reef corals will be displaced by algae as a result of ocean acidification.

Background Artificial intelligence (AI) techniques are increasingly applied to cardiovascular (CV) medicine in arenas ranging from genomics to cardiac imaging analysis. Cardiac Phase Space Tomography Analysis (cPSTA), employing machine-learned linear models from an elastic net method optimized by a genetic algorithm, analyzes thoracic phase signals to identify unique mathematical and tomographic features associated with the presence of flow-limiting coronary artery disease (CAD). This novel approach does not require radiation, contrast media, exercise, or pharmacological stress. The objective of this trial was to determine the diagnostic performance of cPSTA in assessing CAD in patients presenting with chest pain who had been referred by their physician for coronary angiography. Methods This prospective, multicenter, non-significant risk study was designed to: 1) develop machine-learned algorithms to assess the presence of CAD (defined as one or more ≥ 70% stenosis, or fractional flow reserve ≤ 0.80) and 2) test the accuracy of these algorithms prospectively in a naive verification cohort. This report is an analysis of phase signals acquired from 606 subjects at rest just prior to angiography. From the collective phase signal data, features were extracted and paired with the known angiographic results. A development set, consisting of signals from 512 subjects, was used for machine learning to determine an algorithm that correlated with significant CAD. Verification testing of the algorithm was performed utilizing previously untested phase signals from 94 subjects. Results The machine-learned algorithm had a sensitivity of 92% (95% CI: 74%-100%) and specificity of 62% (95% CI: 51%-74%) on blind testing in the verification cohort. The negative predictive value (NPV) was 96% (95% CI: 85%-100%). Conclusions These initial multicenter results suggest that resting cPSTA may have comparable diagnostic utility to functional tests currently used to assess CAD without requiring cardiac stress (exercise or pharmacological) or exposure of the patient to radioactivity.

We present a method for automating the measurement of upper thermal limits in small aquatic organisms. Upper thermal limits are frequently defined by the cessation of movement at high temperature, with measurement being performed by manual observation. Consequently, estimates of upper thermal limits may be subject to error and bias, both within and among observers. Our method utilises video-based tracking software to record the movement of individuals when exposed to high, lethal temperatures. We develop an algorithm in the R computing language that can objectively identify the loss of locomotory function from tracking data. Using independent experimental data, we validate our approach by demonstrating the expected response in upper thermal limits to acclimation temperature. © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Machine learning utilizing convolutional neural networks and elastic net combined with a novel cardiac phase space tomography (cPST) now permits rapid analysis of thoracic phase signals for the assessment of coronary artery disease. This new approach does not require radiation, exercise, or

Both the environments experienced by a mother as a juvenile and an adult can affect her investment in offspring. However, the implications of these maternal legacies, both juvenile and adult, for offspring fitness in natural populations are unclear. We investigated whether the juvenile growth rate and adult reproductive traits (length, body condition, and reproductive investment at spawning) of female wild Atlantic salmon (Salmo salar) were related to the growth and survival of their offspring. Adult salmon captured on their upstream migration were used to create experimental full-sib clutches of eggs, which were mixed and then placed in artificial nests in a natural stream that lacked salmon due to a migration barrier. Four months later we resampled the stream to obtain family-level estimates of offspring size and survival. Mothers that had grown slowly as juveniles (as determined by scalimetry) but had invested heavily in reproduction (egg production for a given body length) and were in relatively poor body condition (somatic mass for a given body length) at spawning produced the largest eggs. Larger eggs resulted in larger juveniles and higher juvenile survival. However, after controlling for egg size, offspring growth was positively related to maternal juvenile growth rate and reproductive investment. The predictors of offspring survival (i.e., reproductive success) varied with the juvenile growth rate of the mother: If females grew slowly as juveniles, their reproductive success was negatively related to their own body condition. In contrast, the reproductive success of females that grew quickly as juveniles was instead related positively to their own body condition. Our results show that maternal influences on offspring in the wild can be complex, with reproductive success related to the early life performance of the mother, as well as her state at the time of breeding.

All NHS hospital trusts are required to operate morbidity and mortality (M&M) meetings as a part of their clinical governance. Typically, these review deaths occurring among inpatients and are regarded as an important patient safety measure despite heterogeneous approaches and a lack of proven

We investigated the independent effects of age at smolting and body condition at the time of spawning on egg production by female Atlantic salmon (Salmo salar). For a given body size, female salmon that had smolted as juveniles after 2 years in fresh water produced smaller, more numerous eggs than females that smolted 1 year later. Furthermore, fecundity (but not egg size) was related positively to maternal body condition at spawning. Given that age at smolting is closely related to juvenile growth rate; results from this study suggest that conditions experienced by female Atlantic salmon during both early life and adulthood have implications for the size and number of eggs that they produce.

Individual differences in the energy cost of self-maintenance (resting metabolic rate, RMR) are substantial and the focus of an emerging research area. These differences may influence fitness because self-maintenance is considered as a life-history component along with growth and reproduction. In this review, we ask why do some individuals have two to three times the ‘maintenance costs’ of conspecifics, and what are the fitness consequences? Using evidence from a range of species, we demonstrate that diverse factors, such as genotypes, maternal effects, early developmental conditions and personality differences contribute to variation in individual RMR. We review evidence that RMR is linked with fitness, showing correlations with traits such as growth and survival. However, these relationships are modulated by environmental conditions (e.g. food supply), suggesting that the fitness consequences of a given RMR may be context-dependent. Then, using empirical examples, we discuss broad-scale reasons why variation in RMR might persist in natural populations, including the role of both spatial and temporal variation in selection pressures and trans-generational effects. To conclude, we discuss experimental approaches that will enable more rigorous examination of the causes and consequences of individual variation in this key physiological trait.

This study demonstrated that, irrespective of hormone type or dose, administering cocoa butter implants during egg development affected the growth of female brown trout Salmo trutta and reduced the size of their offspring. Cortisol treatment also increased adult mortality. Caution is urged in the use of implants for studies of maternal hormonal influences on adult fishes and their offspring. (C) 2011 Crown Copyright Journal of Fish Biology (C) 2011 The Fisheries Society of the British Isles

Summary 1. Social status can vary considerably among individuals and has significant implications for performance. In addition to a genetic component, social status may be influenced by environmental factors including maternal effects such as prenatal hormone exposure. Maternal effects on traits determining social status have previously been examined in species where mothers provide parental care for relatively few offspring and therefore directly influence postnatal development. However, the generality of conclusions arising from these investigations is unclear because species that employ different reproductive strategies have not been studied. 2. We investigated the hypothesis that egg steroid hormone levels influence the social status of juvenile brown trout (Salmo trutta). We manipulated intra-clutch levels of cortisol and testosterone in eggs from 15 mothers using dilute hormone baths at the time of fertilization and examined their effects on traits that correlate with social status in juveniles [including standard body size, aggression, competitive ability and standard metabolic rate (SMR)]. 3. Hormone treatment did not affect whole-animal or mass-corrected SMR at the critical developmental stage when juveniles switch from reliance on a maternally provisioned yolk sac to independent feeding. However, juveniles from cortisol-treated eggs were smaller at this developmental stage. They were also less aggressive than, and subordinate to, fish from untreated eggs in socially competitive conditions, even after correcting for the observed effect of cortisol on body size. Egg testosterone treatment resulted in a likely pharmacological or toxicological dose with subsequent effects on both body size and behaviour in independently feeding juveniles. 4. Results from this study demonstrate that variation in the amount of cortisol deposited in eggs by spawning females influences juvenile social status and performance. The effects of elevated egg cortisol in fish are similar to the actions of embryonic glucocorticoids reported in other vertebrate taxa with very different reproductive strategies, suggesting a widespread mechanism for the effects of maternal stress on offspring. Possible adaptive aspects of this relationship are discussed.

Machine learning through convolutional neural networks and elastic net combined with a novel form of cardiac phase space tomography (cPST) now permits rapid analysis of thoracic phase signals for the assessment of coronary artery disease (CAD). Single photon emission computed tomography (SPECT) is

The article explores the problems associated with the regulation of police powers of detention and questioning as prescribed by the Police and Criminal Evidence Act 1984 (PACE). The police powers of detention and questioning are analysed holistically with reference to the role of the custody officer as gatekeeper, the detention reviews, the treatment and rights of detainees, and the investigative interviewing process. Whilst the fundamental purpose of police powers of detention and questioning is to investigate crime, it is argued that the deficiency in their regulation is a conceptual failure to realise that the process of police investigation militates against objective regulation. The authors argue that PACE is too reliant on self-regulation of police observation and supervision of the rules and a redefinition of the regulation of investigative powers is missing.

A new pedestrian crossing opened in 2015 to visitors of Harlech Castle providing level access to the castle from the newly opened visitor centre. The installation of the new footbridge was possibly the most ambitious construction project to take place at Harlech since the building of the castle itself. This paper details how the client’s aspirations for the footbridge have been fulfilled by the designers, the fabricator and the wider construction team and the challenges they all faced to ensure the scheme made a successful contribution to the local econony.

Fertilised eggs, stage one and stage two juveniles of the smooth marron, Cherax cainii, are attached to the pleopods of the gravid female via specialised structures. The eggs are fixed to the maternal pleopods by egg stalks, whereas stage one and stage two juveniles remain attached by recurved spines on the dactyls of their fourth and fifth pereopods. Crayfish of the third juvenile stage are independent of the mother and receive no maternal care; their dactyl spines are straight and cannot grasp the mother's pleopods; the female displays agonistic behaviour toward her young commencing with stage III instars. We suggest that eggs and the first two juvenile stages attached to the mother would experience reduced levels of predation and be secured against strong river flow. We conclude by reviewing, briefly, the potential fitness costs and benefits of maternal care, to the mother and young of freshwater crayfish, from a life-history perspective.

The consequences of early developmental conditions for performance in later life are now subjected to convergent interest from many different biological sub-disciplines. However, striking data, largely from the biomedical literature, show that environmental effects experienced even before conception can be transmissible to subsequent generations. Here, we review the growing evidence from natural systems for these cross-generational effects of early life conditions, showing that they can be generated by diverse environmental stressors, affect offspring in many ways and can be transmitted directly or indirectly by both parental lines for several generations. In doing so, we emphasize why early life might be so sensitive to the transmission of environmentally induced effects across generations. We also summarize recent theoretical advancements within the field of developmental plasticity, and discuss how parents might assemble different ‘internal’ and ‘external’ cues, even from the earliest stages of life, to instruct their investment decisions in offspring. In doing so, we provide a preliminary framework within the context of adaptive plasticity for understanding inter-generational phenomena that arise from early life conditions.

The various models of the role of the personnel function tend to allude only in part, if at all, to personnel's role in change management. In examining personnel's role in change processes, the authors devised a five-fold model or typology—the ‘charabanc of change’, based on a metaphorical coach journey designed to capture the dynamic, mobile qualities of change. Early research demonstrated that the model was valid and comprehensible for both personnel practitioners and employees in general, and that the ‘navigator's’ role was likely to be an appropriate one for a personnel specialist involved in organizational change. This article: —Briefly reviews the changing role of personnel—over time, between organisations and within organizations; —recaps on existing models of the function; —delineates the ‘charabanc of change’ typology; —reports on the initial research, based on the management change initiative ‘Investors in People’ at a large UK hospital. The authors conclude that the effectiveness of their metaphorical typology rests on: the ease with which the analogy is grasped; the degree to which it is capable of further extension; and its value as a heuristic device leading to deeper levels of understanding of personnel's role in change initiatives. They consider that an area for further research would involve utilizing the ‘charabanc of change’ model to investigate the combinations of roles that are exhibited by the personnel function in an organization undergoing change. © 1998 John Wiley & Sons, Ltd.

Some beta-blockers are less effective in reducing central blood pressure than other antihypertensive drugs, which may explain the higher rate of events in subjects randomized to atenolol in recent trials. We hypothesized that nebivolol, a mixed beta-blocker/nitro-vasodilator, would be more effective than atenolol in reducing central blood pressure and augmentation index (AIx). The aim of the present study was to test this in a double-blind, randomized, cross-over study, in a cohort of subjects with isolated systolic hypertension.Following a 2-week placebo run-in, 16 never-treated hypertensive subjects received atenolol (50 mg), nebivolol (5 mg) and placebo, each for 5 weeks, in a random order. Seated brachial blood pressure and heart rate were measured. Aortic blood pressure, AIx and pulse wave velocity (PWV) were assessed non-invasively.The placebo-corrected fall in brachial pressure was similar between nebivolol and atenolol, as was the reduction in PWV (mean change +/- SEM: -1.0 +/- 0.3 and -1.2 +/- 0.2 m/s; P = 0.2). However, there was less reduction in heart rate (-19 +/- 2 versus -23 +/- 2 beats/min; P0.01) and increase in AIx (+6 +/- 1 versus +10 +/- 1%; P = 0.04), following nebivolol. Aortic pulse pressure was significantly lower (50 +/- 2 versus 54 +/- 2 mmHg; P = 0.02) after nebivolol. N-terminal pro-B-type natriuretic peptide (proBNP) rose on both drugs (100 +/- 33 versus 75 +/- 80 pg/ml; P0.01 for both, NS for comparison).Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. However, nebivolol reduces aortic pulse pressure more than atenolol, which may be related to a less pronounced rise in AIx and bradycardia. Whether this will translate into differences in clinical outcome requires further investigation.

Statistical Energy Analysis (SEA) has traditionally been effective at predicting the transmission of acoustic power between structure and fluid and acoustic transmission between two fluids through a plate. Until recently, SEA has been less effective at predicting the vibrational power transmission directly between structural components. Modern predictive SEA, incorporating multi-wave beam and shell subsystems and more sophisticated models of the dynamics of structural joints, is better equipped to predict the direct vibration transmission problem. We compare predictions using the modern predictive SEA code AutoSEA with measurements of noise and vibration response on a carefully constructed laboratory test structure that incorporates some of the complexities seen in real aerospace structural-acoustic design applications. The test structure consists of 26 plates bounding five interior acoustic cavities, and connected together by “L” and “T” section beam-like elements. A series of comparisons between predictive SEA and test include both structural vibration and interior sound-pressure-level response to structural excitation. These calculations and comparisons reveal uncertainties and biases in the predictions that are significant but small enough to allow the method to be used with confidence.

A beam which is line-connected to a plate is a commonly encountered arrangement in structure-borne noise studies (Figure 1). The modeling of the transmission of vibrational energy through this assembly using Statistical Energy Analysis (SEA) raises several issues. [1]

We investigated whether among-sibling differences in the phenotypes of juvenile fish were systematically related to the position in the egg mass where each individual developed during oogenesis. We sampled eggs from the front, middle and rear thirds of the egg mass in female brown trout of known dominance rank. In the resulting juveniles, we then measured traits that are related to individual fitness: body size, social status and standard metabolic rate (SMR). When controlling for differences among females in mean egg size, siblings from dominant mothers were initially larger (and had a lower mass-corrected SMR) if they developed from eggs at the rear of the egg mass. However, heterogeneity in the size of siblings from different positions in the egg mass diminished in lower-ranking females. Location of the egg within the egg mass also affected the social dominance of the resulting juvenile fish, although the direction of this effect varied with developmental age. This study provides the first evidence of a systematic basis for among-sibling differences in the phenotypes of offspring in a highly fecund organism.

The author describes methods of handling medication in resistant patients. He shows us how such methods can aid psychiatrists and nonmedical staff in collaborating against barriers to effective treatment.