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Objective Data Sources Study Design Data Extraction Principal Findings Conclusions This study aims to examine how variation in physicians' treatment decisions for newborn deliveries responds to changes in the hospital‐level norms for obstetric clinical decision‐making.All hospital‐based births in Florida from 2003 through 2017.Difference‐in‐differences approach is adopted that leverages obstetric unit closures as the source of identifying variation to exogenously shift obstetricians to a new, nearby hospital with different propensities to approach newborn deliveries less intensively.Births attributed to physicians continuously observed 2 years before the closure event and 2 years after the closure event (treatment group physicians) or for identical time periods around a randomly assigned placebo closure date (control group physicians).All of the physicians meeting our inclusion criteria shifted their births to a new hospital less than 20 miles from the hospital shuttering its obstetric unit. The new hospitals approached newborn births more conservatively, and treatment group physicians sharply became less aggressive in their newborn birth clinical management (e.g., use of C‐section). The immediate 11‐percentage point (33%) increase in delivering newborns without any procedure behavior change is statistically significant (p value <0.01) and persistent after the closure event; however, the physicians' payer and patient mix are unchanged.Obstetric physician behavior change appears highly malleable and sensitive to the practice patterns of other physicians delivering newborns at the same hospital. Incentives and policies that encourage more appropriate clinical care norms hospital‐wide could sharply improve physician treatment decisions, with benefits for maternal and infant outcomes. [ABSTRACT FROM AUTHOR]

In internal fertilisers, the precise timing of ovulation with the arrival of sperm at the site of fertilisation is essential for fertilisation success. In birds, mating is often not synchronised with ovulation, but instead females utilise specialised sperm storage tubules (SSTs) in the reproductive tract, which can ensure sperm are always available for fertilisation at the time of ovulation, whilst simultaneously providing a mechanism of post‐copulatory sexual selection. Despite the clear importance of SSTs for fertilisation success, we know little about the mechanisms involved in sperm acceptance, storage, and release. Furthermore, most research has been conducted on only a small number of species, based on which SSTs are usually assumed to look and function in the same way across all species. Here, we conduct a comparative exploration of SST morphology across 26 species of Galliformes. We show that SSTs, and the surrounding tissue, can vary significantly in morphology across species. We provide observational evidence that Galliformes exhibit at least 5 distinct categories of tubule types, including distinctive coiled and multi‐branched tubules, and describe 2 additional features of the surrounding tissue. We suggest functional explanations for variation in tubule morphology and propose next steps for future research. Our findings indicate that SSTs are likely to be far more variable than has previously been assumed, with potentially important consequences for our understanding of sperm storage in birds and post‐copulatory sexual selection in general. [ABSTRACT FROM AUTHOR]

Aim: Species responses to global warming will depend on intraspecific diversity, yet studies of factors governing biogeographic patterns of variability are scarce. Here, we investigate the evolutionary processes underlying genetic and phenotypic diversity in the flightless and cold‐adapted grasshopper Sigaus piliferus, and project its suitable space in time. Location: Te Ika‐a‐Māui Aotearoa—North Island of New Zealand. Methods: We used mitochondrial sequences to investigate population connectivity and demographic trends using phylogeographic tools and neutrality statistics. Metric data were used to document phenotypic variation using naïve clustering. We used niche metrics to assess intraspecific niche variation, and niche modelling to investigate suitability under past and future scenarios. Multiple matrix regressions with randomization explored the processes contributing to phenotypic differentiation among grasshopper populations. Results: Niche models and demographic analyses suggest suitable space for this grasshopper was more restricted during glacial than interglacial stages. Genealogical relationships among ND2 haplotypes revealed a deep north–south split partly concordant with phenotypic and niche variation, suggesting two ecotypes that have mixed during recolonisation of the central volcanic region. Multiple matrix regressions with randomization indicate a link between climate and phenotypic differentiation inferred from leg and pronotum dimensions but not pronotum shape. Niche projections predict severe habitat reduction due to climate warming. Main conclusions: The current distribution and intraspecific diversity of S. piliferus reflect complex biogeographical scenarios consistent with Quaternary climates and volcanism. Phenotypic divergence appears adaptive. Current levels of genetic and phenotypic variation suggest adaptive potential, yet the pace of anthropogenic warming over the next 50 years could result in small populations that may collapse before adapting. Differences in niche features between diverging intraspecific lineages suggest distinct responses to climate change, and this has implications for prioritising conservation actions and management strategies. [ABSTRACT FROM AUTHOR]

Geothermal heat flow is a key parameter in governing ice dynamics, via its influence on basal melt and sliding, englacial rheology, and erosion. It is expected to exhibit significant lateral variability across Antarctica. Despite this, surface heat flow derived from Earth's interior remains one of the most poorly constrained parameters controlling ice sheet evolution. To obtain a continent‐wide map of Antarctic heat supply at regional‐scale resolution, we estimate upper mantle thermomechanical structure directly from VS. Until now, direct inferences of Antarctic heat supply have assumed constant crustal composition. Here, we explore a range of crustal conductivity and radiogenic heat production values by fitting thermodynamically self‐consistent geotherms to their seismically inferred counterparts. Independent estimates of crustal conductivity derived from VP are integrated to break an observed trade‐off between crustal parameters, allowing us to infer Antarctic geothermal heat flow and its associated uncertainty. Plain Language Summary: The future evolution of the Antarctic Ice Sheet depends on its stability, which describes how sensitive it is to environmental change. A key factor influencing ice sheet stability is how much thermal energy is transferred into its base from Earth's interior: a parameter called geothermal heat flow. If the level of heat supply is high, melting at the base of the ice sheet is encouraged, resulting in enhanced sliding toward outlet glaciers at the continental perimeter. Consequently, ice loss is accelerated, and the likelihood of glacial collapse is increased. Therefore, an accurate map of Antarctic geothermal heat flow, including how this parameter varies from region to region, is needed to produce high quality projections of Antarctic ice mass loss and therefore global sea level change. In this study, we use models of how seismic wave speed varies within Earth to estimate its three‐dimensional temperature structure, as well as its thermal conductivity. These data are used to infer a collection of best‐fitting models of Earth's thermal state, and hence estimate Antarctic geothermal heat flow. Key Points: Demonstration of new methodology for inferring geothermal heat flow from seismological dataS‐ and P‐wave velocity used together to infer and fit geothermsIncorporation of laterally varying crustal conductivity and heat production [ABSTRACT FROM AUTHOR]

Demographic histories are frequently a product of the environment, as populations expand or contract in response to major environmental changes, often driven by changes in climate. Meso‐ and bathy‐pelagic fishes inhabit some of the most temporally and spatially stable habitats on the planet. The stability of the deep‐pelagic could make deep‐pelagic fishes resistant to the demographic instability commonly reported in fish species inhabiting other marine habitats, however the demographic histories of deep‐pelagic fishes are unknown. We reconstructed the historical demography of 11 species of deep‐pelagic fishes using mitochondrial and nuclear DNA sequence data. We uncovered widespread evidence of population expansions in our study species, a counterintuitive result based on the nature of deep‐pelagic ecosystems. Frequency‐based methods detected potential demographic changes in nine species of fishes, while extended Bayesian skyline plots identified population expansions in four species. These results suggest that despite the relatively stable nature of the deep‐pelagic environment, the fishes that reside here have likely been impacted by past changes in climate. Further investigation is necessary to better understand how deep‐pelagic fishes, by far Earth's most abundant vertebrates, will respond to future climatic changes. [ABSTRACT FROM AUTHOR]

Demographic histories are frequently a product of the environment, as populations expand or contract in response to major environmental changes, often driven by changes in climate. Meso‐ and bathy‐pelagic fishes inhabit some of the most temporally and spatially stable habitats on the planet. The stability of the deep‐pelagic could make deep‐pelagic fishes resistant to the demographic instability commonly reported in fish species inhabiting other marine habitats, however the demographic histories of deep‐pelagic fishes are unknown. We reconstructed the historical demography of 11 species of deep‐pelagic fishes using mitochondrial and nuclear DNA sequence data. We uncovered widespread evidence of population expansions in our study species, a counterintuitive result based on the nature of deep‐pelagic ecosystems. Frequency‐based methods detected potential demographic changes in nine species of fishes, while extended Bayesian skyline plots identified population expansions in four species. These results suggest that despite the relatively stable nature of the deep‐pelagic environment, the fishes that reside here have likely been impacted by past changes in climate. Further investigation is necessary to better understand how deep‐pelagic fishes, by far Earth's most abundant vertebrates, will respond to future climatic changes. [ABSTRACT FROM AUTHOR]

Background: Dermal fillers have created a multi‐billion‐dollar industry. They are the second most popular form of injectable, as they primarily address volume loss, augmentation, and provide immediate results. The most popular form includes hyaluronic acid‐based fillers, however, alternatives exist. Objective: To create clinical charts to help with filler selection, injection, and addressing common complications. Methods: The current literature and expert opinions form our two senior authors were used to create a numerical and color‐coded chart based on G‐prime for filler selection, as well as an anatomical table with current recommendations and pearls. We have also included a safety table with current clinical recommendation to deal with common filler‐related complications. Conclusion: Fillers are a safe and reliable method to achieve augmentation. Filler selection in various anatomical planes plays a significant role in achieving favorable results. [ABSTRACT FROM AUTHOR]

Plant growth is influenced by interactions with neighbouring plants. The strength and direction of the cumulative neighbourhood effect on growth can depend on neighbour properties, such as their abundance, size and proximity, as well as the degree of similarity between interacting plants and their traits, which can be captured by the species identity of neighbours. Such interactions are also influenced by the local environmental conditions that are largely determined by climate. Because neighbour and climatic effects are typically explored in isolation, particularly in long‐lived species such as trees, it is unclear how the impacts of neighbours on plant growth shift in response to temporal variation in climatic conditions.Here, we explored how neighbouring plants impact the annual growth of two eucalypts, Eucalyptus delegatensis and Eucalyptus regnans, over three growing seasons in an experimental forest in south‐east Tasmania, Australia. We assessed whether eucalypt growth rates could be described by the number, size, proximity, and species identity of neighbours, and how the strength of this effect was influenced by the growing season climatic conditions.We found that climate and neighbouring plants had an interactive impact on eucalypt growth. Neighbours had a consistent, competitive effect on the growth of both eucalypts in all three growing seasons which was strongly related to the cumulative neighbourhood biomass. The identity of neighbours was important in determining E. regnans growth only, whereby distinguishing neighbours according to functional group best described growth. Over all three growing seasons, we predicted that, on average, neighbours reduced E. delegatensis and E. regnans mean annual growth by 60.5% and 48.4%, respectively. However, the strength of the competitive effect of neighbours on eucalypt growth was related to growing season climate, being strongest when conditions were hot and dry and weakest in cool, wet conditions.Synthesis: Given the consistent results observed in two co‐occurring eucalypts, our findings suggest that drier and hotter climatic conditions increase the strength of competitive effects on tree growth. This has implications for future forest productivity given projected increased temperatures and variation in rainfall patterns globally. [ABSTRACT FROM AUTHOR]

The article discusses the HF-REVERT trial, which is the first trial to test the efficacy and safety of an antisense oligonucleotide (ASO) in heart failure (HF). The trial focuses on patients with reduced left ventricular ejection fraction (LVEF) after a myocardial infarction (MI). The ASO being tested, CDR132L, suppresses microRNA (miR)-132-3p, which is known to exacerbate adverse cardiac remodeling. The primary endpoint of the trial is the change in echocardiographic left ventricular end-systolic volume index at 6 months. The article highlights the potential of manipulating non-coding RNAs as a new therapeutic strategy for HF. [Extracted from the article]

Sea surface temperatures (SSTs) vary not only due to heat exchange across the air‐sea interface but also due to changes in effective heat capacity as primarily determined by mixed layer depth (MLD). Here, we investigate seasonal and regional characteristics of the contribution of MLD anomalies to the month‐to‐month variability of SST using observational datasets. First, we propose a metric called Flux Divergence Angle, which can quantify the relative contributions of surface heat fluxes and MLD anomalies to SST variability. Using this metric, we find that MLD anomalies tend to amplify SST anomalies in the extra‐tropics, especially in the eastern ocean basins, during spring and summer. In contrast, MLD anomalies tend to suppress SST anomalies in the eastern tropical Pacific during December‐January‐February. This paper provides the first global picture of the observed importance of MLD anomalies to the local SST variability. Plain Language Summary: Sea surface temperature (SST) is one of the important indicators as well as drivers of climate variability over the globe. SST varies not only due to changes in surface heat fluxes but also due to changes in effective heat capacity as mainly determined by mixed layer depth (MLD). However, the observed characteristics of the latter process associated with the MLD anomalies are limited. In this study, we propose a new metric called "Flux Divergence Angle (FDA)," which can quantify the relative importance of MLD and surface heat flux to the SST variability. Using this metric, we find that the MLD anomalies tend to amplify the local SST variability in the extra‐tropics during spring and summer. On the other hand, MLD anomalies tend to suppress the SST variability in the eastern tropical Pacific during December‐January‐February. This paper provides, for the first time, the global picture of relative importance of MLD anomalies to the SST variability based on observations. Key Points: Relative contributions of mixed layer depth (MLD) and surface heat flux anomalies to sea surface temperature (SST) variability are investigated using the Flux Divergence Angle metricMLD anomalies tend to amplify SST anomalies in the extra‐tropics, especially in eastern part of ocean basin, during the spring and summerMLD anomalies tend to suppress SST anomalies in the eastern tropical Pacific during December‐January‐February [ABSTRACT FROM AUTHOR]

Interactions among neighbouring plants are key determinants of plant growth. To characterise the cumulative effect of all neighbours on the growth of a focal plant, neighbourhoods are often described by 'competition' indices. Common competition indices calculate the summed size of neighbour plants (focal‐independent index [FII]) whilst others include the summed ratio of the neighbour size relative to focal plant size (focal dependent). A frequently overlooked statistical artefact is that focal‐dependent indices (FDIs) may lead to biased estimates of neighbourhood effects on plant growth when growth is size dependent.Here, we conduct a literature search to determine the most common index types used to explain neighbour effects on tree growth. We then assess the ability of two common index types—focal dependent and focal independent—to correctly infer neighbourhood effects in (1) observations of tree growth in an experimental forest in south‐east Tasmania, Australia, and (2) an artificially created dataset where tree growth is unrelated to the neighbourhood.Both indices detected the competitive neighbourhood effect on tree growth observed in our own dataset but differed in their conclusion regarding neighbour effects in the simulated data. Despite the simulated dataset being generated so there was no relationship between tree growth and their neighbourhood, the FDI detected strong, competitive neighbourhood effects when intrinsic growth was incorrectly related to tree size. In contrast, when we considered the FII as the neighbourhood metric, we correctly did not detect any neighbourhood effects in the simulated data regardless of how size‐dependent growth was described.Synthesis. 'Competition' indices are a useful method to characterise the cumulative neighbourhood effect on plant growth; however, we demonstrate that indices which include the size of the focal plant in their calculation can be biased by an inherent relationship between tree growth and initial size. Whilst this bias typically overstates the strength of competition in determining focal tree growth, we show that it can be mitigated by correctly describing intrinsic growth. We discuss the limitations of both index types, provide recommendations for performing statistical modelling and outline how to check for accurate neighbour inference. [ABSTRACT FROM AUTHOR]

Arterial occlusion pressure (AOP) is influenced by the characteristics of the cuff used to measure AOP. Doppler ultrasound was used to measure AOP of the brachial and superficial femoral arteries using straight and curved blood flow restriction cuffs in 21 males and 21 females. Vessel diameter and blood flow were evaluated as independent predictors of AOP. Overall, there were no significant differences in AOP when using the straight and curved cuffs in the brachial (129 mmHg vs. 128 mmHg) or superficial femoral artery (202 mmHg vs. 200 mmHg), respectively. Overall, AOP was greater (p < 0.05) in males than in females in the arm (135 mmHg, 123 mmHg) and leg (211 mmHg, 191 mmHg). Brachial (0.376 mm, 0.323 mm) and superficial femoral (0.547 mm, 0.486 mm) arteries were larger (p = 0.016) in males than in females, respectively. Systolic blood pressure (SBP) and arm circumference were predictive of brachial artery AOP, whereas SBP, diastolic blood pressure, thigh circumference, and vessel diameter were predictive of superficial femoral artery AOP. Straight and curved cuffs are efficacious in the measurement of AOP in the arm and leg. Differences in vessel size may contribute to sex differences in AOP but this requires further investigation. [ABSTRACT FROM AUTHOR]

Disease ecologists now recognize the limitation behind examining host–parasite interactions in isolation: community members—especially predators—dramatically affect host–parasite dynamics. Although the initial paradigm was that predation should reduce disease in prey populations ("healthy herds hypothesis"), researchers have realized that predators sometimes increase disease in their prey. These "predator–spreaders" are now recognized as critical to disease dynamics, but empirical research on the topic remains fragmented. In a narrow sense, a "predator–spreader" would be defined as a predator that mechanically spreads parasites via feeding. However, predators affect their prey and, subsequently, disease transmission in many other ways such as altering prey population structure, behavior, and physiology. We review the existing evidence for these mechanisms and provide heuristics that incorporate features of the host, predator, parasite, and environment to understand whether or not a predator is likely to be a predator–spreader. We also provide guidance for targeted study of each mechanism and quantifying the effects of predators on parasitism in a way that yields more general insights into the factors that promote predator spreading. We aim to offer a better understanding of this important and underappreciated interaction and a path toward being able to predict how changes in predation will influence parasite dynamics. [ABSTRACT FROM AUTHOR]

Background: The perspective and experiences of individuals with Parkinson's disease (PD) regarding genetic testing is limited. Objectives: To determine if anticipated benefits and negative consequences of genetic testing noted in prior studies have occurred in a surveyed group of patients with PD and to identify reasons why some individuals with PD have not had testing. Methods: Individuals were surveyed from 22 support/advocacy groups throughout the US. Information about patient demographics and genetic testing were assessed, along with the consequences experienced after testing or anticipated by those who have not had testing. Descriptive statistics, Pearson correlation coefficient, ANOVA, and independent sample t‐test were utilized for data analysis. Results: Of the genetic testing group (n = 78), most received testing through a research study (44.9%) or a Direct‐to‐Consumer company (46.2%). Most did not meet with a genetic counselor before (87.2%) or after testing (64.1%). Fewer positive and fewer negative consequences were reported after testing compared to the consequences anticipated by those who have not undergone testing (P < 0.001, all comparisons). Of the non‐genetic testing group (n = 166), 49.4% did not undergo testing because they were not aware it was available and 38.0% because their doctor did not offer it. Conclusions: Findings demonstrate the need for providers to have genetic testing discussions with PD patients, who may otherwise seek testing via Direct‐to‐Consumer companies or be unaware it is available. Collaborations with genetic counselors trained in providing anticipatory guidance may assist patients in forming more realistic expectations regarding the consequences experienced after genetic testing for PD. [ABSTRACT FROM AUTHOR]

Major aridification events in Australia during the Pliocene may have had significant impact on the distribution and structure of widespread species. To explore the potential impact of Pliocene and Pleistocene climate oscillations, we estimated the timing of population fragmentation and past connectivity of the currently isolated but morphologically similar subspecies of the widespread brushtail possum (Trichosurus vulpecula). We use ecological niche modeling (ENM) with the current fragmented distribution of brushtail possums to estimate the environmental envelope of this marsupial. We projected the ENM on models of past climatic conditions in Australia to infer the potential distribution of brushtail possums over 6 million years. D‐loop haplotypes were used to describe population structure. From shotgun sequencing, we assembled whole mitochondrial DNA genomes and estimated the timing of intraspecific divergence. Our projections of ENMs suggest current possum populations were unlikely to have been in contact during the Pleistocene. Although lowered sea level during glacial periods enabled connection with habitat in Tasmania, climate fluctuation during this time would not have facilitated gene flow over much of Australia. The most recent common ancestor of sampled intraspecific diversity dates to the early Pliocene when continental aridification caused significant changes to Australian ecology and Trichosurus vulpecula distribution was likely fragmented. Phylogenetic analysis revealed that the subspecies T. v. hypoleucus (koomal; southwest), T. v. arnhemensis (langkurr; north), and T. v. vulpecula (bilda; southeast) correspond to distinct mitochondrial lineages. Despite little phenotypic differentiation, Trichosurus vulpecula populations probably experienced little gene flow with one another since the Pliocene, supporting the recognition of several subspecies and explaining their adaptations to the regional plant assemblages on which they feed. [ABSTRACT FROM AUTHOR]

B This article refers to 'Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation' by K. Oyama I et al i ., published in this issue on pages 832-841. b The incidence and prevalence of atrial fibrillation (AF), by far the most common cardiac arrhythmia, has risen over the last 30 years. Therefore, this data set offers no internal comparison of AF and sinus rhythm with respect to the performance of the three markers in predicting HF hospitalization or HF death. [Extracted from the article]

Species richness in tropical forests is correlated with other dimensions of diversity, including the diversity of plant–herbivore interactions and the phytochemical diversity that influences those interactions. Understanding the complexity of plant chemistry and the importance of phytochemical diversity for plant–insect interactions and overall forest richness has been enhanced significantly by the application of metabolomics to natural systems. The present work used proton nuclear magnetic resonance spectroscopy (1H‐NMR) profiling of crude leaf extracts to study phytochemical similarity and diversity among Piper plants growing naturally in the Atlantic Rainforest of Brazil. Spectral profile similarity and chemical diversity were quantified to examine the relationship between metrics of phytochemical diversity, specialist and generalist herbivory, and understory plant richness. Herbivory increased with understory species richness, while generalist herbivory increased and specialist herbivory decreased with the diversity of Piper leaf material available. Specialist herbivory increased when conspecific host plants were more spectroscopically dissimilar. Spectral similarity was lower among individuals of common species, and they were also more spectrally diverse, indicating phytochemical diversity is beneficial to plants. Canopy openness and soil nutrients also influenced chemistry and herbivory. The complex relationships uncovered in this study add information to our growing understanding of the importance of phytochemical diversity for plant–insect interactions and tropical plant species richness. [ABSTRACT FROM AUTHOR]

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non‐coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long‐term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling. [ABSTRACT FROM AUTHOR]

Objective: To examine how variation in the size of the local Medicaid population moderates Medicaid‐to‐private treatment access differentials for women with opioid use disorder (OUD). Data Sources: County‐level information on total Medicaid enrollment combined with randomized field experiment data from 10 diverse states that used a simulated patient (audit) methodology to examine buprenorphine providers' appointment granting behavior. Study Design: We used multiple regression modeling approaches to capture the moderating influence of Medicaid prevalence on differences in the likelihood of receiving an insurance‐covered appointment between Medicaid and privately insured female patients. Data Extraction: Completed calls to buprenorphine treatment providers. Principal Findings: We find a 0.37 percentage point (p value <0.01) narrowing of the Medicaid‐to‐private access gap with each one percentage point increase in the local insured population on Medicaid. There is effectively no difference in the likelihood of being granted an insurance‐covered appointment across the two payer groups in the top tercile of Medicaid penetration. Conclusions: When Medicaid is a common source of insurance within the local population, buprenorphine providers are much less likely to discriminate between Medicaid and privately insured prospective patients. Efforts to enhance equitable access across patient groups are perhaps best targeted where Medicaid prevalence is lower. [ABSTRACT FROM AUTHOR]

The study of functional traits offers predictive power for community ecology. Particularly in cases where individual species are difficult to study, known properties of trait spectra, such as the leaf economics spectrum (LES), and trait–environment relationships can provide crucial generalizable information that can contribute to forecasts of distributional shifts in response to the abiotic effects of climate and land use changes.Vascular epiphytes have been proposed as indicators of environmental change, but we know little about the ecology of most species. Key functional trait assumptions are based on terrestrial plants; testing these in epiphytes verifies their universality and will inform applying functional traits in predicting epiphyte responses to climate and land use change.In this study, we use functional traits from 37 vascular epiphyte species from forests and shade coffee farms at two sites in northern Nicaragua. We compare correlations among traits and intraspecific trait variances with those of terrestrial plants and among epiphyte taxonomic groups. We also test trait responses to environmental differences between sites and land use types, and within zones of the tree.We find that epiphyte leaf traits fall towards the slower end of the LES, but with about one‐third lower leaf nitrogen per change in specific leaf area (SLA) relative to terrestrial herbaceous plants. Bromeliads show less relationship between these traits than other epiphyte groups and also deviate in other trait interrelationships, suggesting unique leaf construction.Trait–environment relationships varied most strongly along vertical gradients within trees, but some traits, including SLA and carbon isotope ratio, also responded to land use and site differences.We present evidence that trait relationships established for terrestrial plants appear to translate to epiphytes, but identify some possible caveats. Strong trait response to vertical gradients within trees suggests that within‐canopy shifts could provide resilience to climate and land use changes for some epiphyte species. [ABSTRACT FROM AUTHOR]

Ecological theory suggests that predators can either keep prey populations healthy by reducing parasite burdens or alternatively, increase parasitism in prey. To quantify the overall magnitude and direction of the effect of predation on parasitism in prey observed in practice, we conducted a meta‐analysis of 47 empirical studies. We also examined how study attributes, including parasite type and life cycle, habitat type, study design, and whether predators were able to directly consume prey contributed to variation in the predator‐prey‐parasite interaction. We found that the overall effect of predation on parasitism differed between parasites and parasitoids and that whether consumptive effects were present, and whether a predator was a non‐host spreader of parasites, were the most important traits predicting the parasite response. Our results suggest that the mechanistic basis of predator‐prey interactions strongly influences the effects of predators on parasites and that these effects, although context dependent, are predictable. [ABSTRACT FROM AUTHOR]

Objective: To examine long‐run growth in the ambulatory surgery center (ASC) industry and potential factors influencing its trajectory. Data sources: National data for all Medicare‐certified ASCs (1990–2015) and outpatient discharge records from the state of Florida in 2007. Study Design: We documented the number of ASCs in the United States over time and decomposed the trend into underlying ASC market entry and exit behavior. We then examined the plausibility of 2008 Medicare payment reforms to influence the trend changes. Data Extraction Methods: Data on ASC openings and closures are obtained from the Centers for Medicare and Medicaid Services Provider of Service files. Secondary data on ASC volume in Florida are obtained from the Florida Agency for Health Care Administration. Principal Findings: The number of ASCs in the United States grew 5%–10% annually between 1990 and 2007 but by 1% or less beginning in 2008. This change coincided with substantive reductions in Medicare payments for key ASC services. The annual number of new ASCs was as much as 50% lower following the payment change. Conclusions: ASCs are an important competitor for outpatient services, but growth has slowed dramatically. Sharp changes in new ASC entry align with less generous Medicare fees. [ABSTRACT FROM AUTHOR]

Summary: Parastagonospora nodorum is an economically important necrotrophic fungal pathogen of wheat. Parastagonospora nodorum secretes necrotrophic effectors that target wheat susceptibility genes to induce programmed cell death (PCD). In this study, we cloned and functionally validated SnTox5 and characterized its role in pathogenesis.We used whole genome sequencing, genome‐wide association study (GWAS) mapping, CRISPR‐Cas9‐based gene disruption, gain‐of‐function transformation, quantitative trait locus (QTL) analysis, haplotype and isoform analysis, protein modeling, quantitative PCR, and laser confocal microscopy to validate SnTox5 and functionally characterize SnTox5.SnTox5 is a mature 16.26 kDa protein with high structural similarity to SnTox3. Wild‐type and mutant P. nodorum strains and wheat genotypes of SnTox5 and Snn5, respectively, were used to show that SnTox5 not only targets Snn5 to induce PCD but also facilitates the colonization of the mesophyll layer even in the absence of Snn5.Here we show that SnTox5 facilitates the efficient colonization of the mesophyll tissue and elicits PCD specific to host lines carrying Snn5. The homology to SnTox3 and the ability of SnTox5 to facilitate the colonizing of the mesophyll also suggest a role in the suppression of host defense before PCD induction. See also the Commentary on this article by Kanyuka et al., 233: 11–14. [ABSTRACT FROM AUTHOR]

Summary: Parastagonospora nodorum is a fungal pathogen of wheat. As a necrotrophic specialist, it deploys effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Here we identify and functionally validate the effector targeting the host susceptibility genes Snn2, Snn6 and Snn7.We utilized whole‐genome sequencing, association mapping, gene‐disrupted mutants, gain‐of‐function transformants, virulence assays, bioinformatics and quantitative PCR to characterize these interactions.A single proteinaceous effector, SnTox267, targeted Snn2, Snn6 and Snn7 to trigger PCD. Snn2 and Snn6 functioned cooperatively to trigger PCD in a light‐dependent pathway, whereas Snn7‐mediated PCD functioned in a light‐independent pathway. Isolates harboring 20 SnTox267 protein isoforms quantitatively varied in virulence. The diversity and distribution of isoforms varied between populations, indicating adaptation to local selection pressures. SnTox267 deletion resulted in the upregulation of effector genes SnToxA, SnTox1 and SnTox3.We validated a novel effector operating in an inverse‐gene‐for‐gene manner to target three genetically distinct host susceptibility genes and elicit PCD. The discovery of the complementary gene action of Snn2 and Snn6 indicates their potential function in a guard or decoy model. Additionally, differences in light dependency in the elicited pathways and upregulation of unlinked effectors sheds new light onto a complex fungal necrotroph–host interaction. See also the Commentary on this article by Kanyuka et al., 233: 11–14. [ABSTRACT FROM AUTHOR]

Premise: The distribution of genetic diversity on the landscape has critical ecological and evolutionary implications. This may be especially the case on a local scale for foundation plant species because they create and define ecological communities, contributing disproportionately to ecosystem function. Methods: We examined the distribution of genetic diversity and clones, which we defined first as unique multilocus genotypes (MLG), and then by grouping similar MLGs into multilocus lineages. We used 186 markers from inter‐simple sequence repeats (ISSR) across 358 ramets from 13 patches of the foundation grass Leymus chinensis. We examined the relationship between genetic and clonal diversities, their variation with patch size, and the effect of the number of markers used to evaluate genetic diversity and structure in this species. Results: Every ramet had a unique MLG. Almost all patches consisted of individuals belonging to a single multilocus lineages. We confirmed this with a clustering algorithm to group related genotypes. The predominance of a single lineage within each patch could be the result of the accumulation of somatic mutations, limited dispersal, some sexual reproduction with partners mainly restricted to the same patch, or a combination of all three. Conclusions: We found strong genetic structure among patches of L. chinensis. Consistent with previous work on the species, the clustering of similar genotypes within patches suggests that clonal reproduction combined with somatic mutation, limited dispersal, and some degree of sexual reproduction among neighbors causes individuals within a patch to be more closely related than among patches. [ABSTRACT FROM AUTHOR]

Aim: The growing demand for analgesia, coupled with an increasing need to treat opioid dependence and overdose, has escalated the development of novel opioids. We aimed to quantify the number of opioid drugs developed and to catalogue them based on their pharmacology. Methods: We conducted a systematic search of seven sources in November 2020, including the WHO's Anatomical Therapeutic Classification index, the British National Formulary, the IUPHAR/BPS Guide to Pharmacology, the International Narcotics Control Board Index of Names of Narcotic Drugs, the WHO's International Nonproprietary Names MedNet service, Martindale's Extra Pharmacopoeia and the Merck Index, to include opioid drugs that targeted or had an effect or coeffect at one or more opioid receptors. We extracted chemical and nonproprietary names, drug stems, molecular formulas, molecular weights, receptor targets, actions at opioid receptors and classes based on their origins. We used descriptive statistics and calculated medians and interquartile ranges where appropriate. Results: We identified 233 opioid drugs and created an online resource (https://www.catalogueofopioids.net/). There were 10 unique drug stems, and "‐fentanil" accounted for one‐fifth (20%) of all opioids. Most of the drugs (n = 133) targeted mu‐opioid receptors and the majority (n = 191) were agonists at one or more receptors. Most (82%) were synthetic opioids, followed by semisynthetic opioids (16%) and alkaloids (3%). Conclusion: This catalogue centralizes and disseminates information that could assist researchers, prescribers and the public to improve the safe use of opioids. [ABSTRACT FROM AUTHOR]

Information‐theoretic approaches to model selection, such as Akaike's information criterion (AIC) and cross validation, provide a rigorous framework to select among candidate hypotheses in ecology, yet the persistent concern of overfitting undermines the interpretation of inferred processes. A common misconception is that overfitting is due to the choice of criterion or model score, despite research demonstrating that selection uncertainty associated with score estimation is the predominant influence. Here we introduce a novel selection rule that identifies a parsimonious model by directly accounting for estimation uncertainty, while still retaining an information‐theoretic interpretation. The new rule, which is a modification of the existing one‐standard‐error rule, mitigates overfitting and reduces the likelihood that spurious effects will be included in the selected model, thereby improving its inferential properties. We present the rule and illustrative examples in the context of maximum‐likelihood estimation and Kullback‐Leibler discrepancy, although the rule is applicable in a more general setting, including Bayesian model selection and other types of discrepancy. [ABSTRACT FROM AUTHOR]

The relationship between outgoing longwave radiation (OLR) and the surface temperature has a major influence on Earth's climate sensitivity. Studies often assume that this relationship is approximately linear, but it is unclear whether the approximation always holds. Here we show that, on seasonal timescales, clear‐sky OLR is a multivalued function of local surface temperature. In many places, the OLR‐temperature relationship is better approximated by a loop than a line and we quantify the resulting "OLR loopiness", that is, how much clear‐sky OLR varies between different seasons with the same surface temperature. Based on offline radiative calculations, in the tropics OLR loops are mainly caused by seasonal variations in relative humidity that are out of phase with surface temperature; in the extratropics, OLR loops are mainly due to variations in lapse rates. Our work provides a mechanism through which Earth's climate feedback can differ between seasonal and long‐term time scales. Plain Language Summary: When the Earth is warmer, it loses more heat to space. The simplest formula describing this relationship is a line with an upwards slope, where the slope determines how much Earth warms from added greenhouse gases. Here, we report that the relationship between local temperature and rate of heat loss to space can be more complicated on seasonal time scales, often taking the form of loops or other curved shapes. We come up with a way to measure how big these loops are, and explain why they happen. Our results underline that Earth's response to seasonal changes is generally different from Earth's response to global warming. Key Points: Monthly outgoing longwave radiation (OLR) is a multivalued function of local surface temperature, exhibiting loops and other complex shapesOLR loops occur both in clear‐sky and all‐sky data, so the behavior is robust to cloudsOLR loops arise because humidity lags surface temperature in the tropics, and lapse rates lead to surface temperature in the extratropics [ABSTRACT FROM AUTHOR]

Although riboswitches have long been known to regulate translation initiation and transcription termination, a growing body of evidence indicates that they can also control bacterial RNA lifetimes by acting directly to hasten or impede RNA degradation. Ligand binding to the aptamer domain of a riboswitch can accelerate RNA decay by triggering a conformational change that exposes sites to endonucleolytic cleavage or by catalyzing the self‐cleavage of a prefolded ribozyme. Alternatively, the conformational change induced by ligand binding can protect RNA from degradation by blocking access to an RNA terminus or internal region that would otherwise be susceptible to attack by an exonuclease or endonuclease. Such changes in RNA longevity often accompany a parallel effect of the same riboswitch on translation or transcription. Consequently, a single riboswitch aptamer may govern the function of multiple effector elements (expression platforms) that are co‐resident within a transcript and act independently of one another. [ABSTRACT FROM AUTHOR]

Joint mobility is a key factor in determining the functional capacity of tetrapod limbs, and is important in palaeobiological reconstructions of extinct animals. Recent advances have been made in quantifying osteological joint mobility using virtual computational methods; however, these approaches generally focus on the proximal limb joints and have seldom been applied to fossil mammals. Palorchestes azael is an enigmatic, extinct ~1000 kg marsupial with no close living relatives, whose functional ecology within Australian Pleistocene environments is poorly understood. Most intriguing is its flattened elbow morphology, which has long been assumed to indicate very low mobility at this important joint. Here, we tested elbow mobility via virtual range of motion (ROM) mapping and helical axis analysis, to quantitatively explore the limits of Palorchestes' elbow movement and compare this with their living and extinct relatives, as well as extant mammals that may represent functional analogues. We find that Palorchestes had the lowest elbow mobility among mammals sampled, even when afforded joint translations in addition to rotational degrees of freedom. This indicates that Palorchestes was limited to crouched forelimb postures, something highly unusual for mammals of this size. Coupled flexion and abduction created a skewed primary axis of movement at the elbow, suggesting an abducted forelimb posture and humeral rotation gait that is not found among marsupials and unlike that seen in any large mammals alive today. This work introduces new quantitative methods and demonstrates the utility of comparative ROM mapping approaches, highlighting that Palorchestes' forelimb function was unlike its contemporaneous relatives and appears to lack clear functional analogues among living mammals. [ABSTRACT FROM AUTHOR]

Aim: Seabirds are heavily threatened by anthropogenic activities, and their conservation status is deteriorating rapidly. Nonetheless, these pressures are unlikely to impact all species uniformly. It remains an open question whether seabirds with similar ecological roles are responding similarly to human pressures. Our aims were as follows: (a) to test whether threatened versus non‐threatened seabirds are separated in trait space; (b) to quantify the similarity of species' roles (redundancy) per IUCN Red List Category; and (c) to identify traits that render species vulnerable to anthropogenic threats. Location: Global. Time period: Contemporary. Major taxa studied: Seabirds. Methods: We compile and impute eight traits that relate to species' vulnerabilities and ecosystem functioning across 341 seabird species. Using these traits, we build a mixed‐data principal component analysis of species' trait space. We quantify trait redundancy using the unique trait combinations (UTCs) approach. Finally, we undertake a similarity of percentages analysis to identify which traits explain the greatest difference between threat groups. Results: We find that seabirds segregate in trait space based on IUCN threat status, indicating that anthropogenic impacts are selectively removing large, long‐lived, pelagic surface feeders with narrow habitat breadths. We also find that threatened species have higher trait redundancy, whereas non‐threatened species have relatively limited redundancy. Finally, we find that species with narrow habitat breadths, fast reproductive speeds and varied diets are more likely to be threatened by habitat‐modifying processes (e.g., pollution and natural system modifications), whereas pelagic specialists with slow reproductive speeds and varied diets are vulnerable to threats that directly impact survival and fecundity (e.g., invasive species and biological resource use) and climate change. Species with no threats are non‐pelagic specialists with invertebrate diets and fast reproductive speeds. Main conclusions: Our results suggest that both threatened and non‐threatened species contribute unique ecological strategies. Consequently, conserving both threat groups, but importantly with contrasting approaches, might avoid potential changes in ecosystem functioning and stability. [ABSTRACT FROM AUTHOR]

Background: Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods: Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results: Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA‐125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease‐free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA‐125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA‐125 across the study timepoints (p = 0.47). Conclusions: Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA‐125 could be helpful in recognizing abdominal recurrences. [ABSTRACT FROM AUTHOR]

Summary: The interaction of plants with complex microbial communities is the result of co‐evolution over millions of years and contributed to plant transition and adaptation to land. The ability of plants to be an essential part of complex and highly dynamic ecosystems is dependent on their interaction with diverse microbial communities. Plant microbiota can support, and even enable, the diverse functions of plants and are crucial in sustaining plant fitness under often rapidly changing environments. The composition and diversity of microbiota differs between plant and soil compartments. It indicates that microbial communities in these compartments are not static but are adjusted by the environment as well as inter‐microbial and plant–microbe communication. Hormones take a crucial role in contributing to the assembly of plant microbiomes, and plants and microbes often employ the same hormones with completely different intentions. Here, the function of hormones as go‐betweens between plants and microbes to influence the shape of plant microbial communities is discussed. The versatility of plant and microbe‐derived hormones essentially contributes to the creation of habitats that are the origin of diversity and, thus, multifunctionality of plants, their microbiota and ultimately ecosystems. Significance Statement: Plants and all their tissues are inhabited by, surrounded by and, thus, in interactions with complex microbial communities. Plant hormones drive the establishment of these communities, termed microbiota, which add a diversity of functions to plants that are crucial for plant fitness under changing environments since the time of land colonisation. [ABSTRACT FROM AUTHOR]

A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein–protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)‐based approaches have allowed unbiased mapping of these disease‐mediated changes in protein–protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein–protein interactions at a system‐level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS‐based protein–protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications. [ABSTRACT FROM AUTHOR]

Objective: To describe the cost of using evidence-based implementation strategies for sustained behavioral health integration (BHI) involving population-based screening, assessment, and identification at 25 primary care sites of Kaiser Permanente Washington (2015-2018).Data Sources/study Setting: Project records, surveys, Bureau of Labor Statistics compensation data.Study Design: Labor and nonlabor costs incurred by three implementation strategies: practice coaching, electronic health records clinical decision support, and performance feedback.Data Collection/extraction Methods: Personnel time spent on these strategies was estimated for five broad roles: (a) project leaders and administrative support, (b) practice coaches, (c) clinical decision support programmers, (d) performance metric programmers, and (e) primary care local implementation team members.Principal Finding: Implementation involved 286 persons, 18 131 person-hours, costing $1 587 139 or $5 per primary care visit with screening or $38 per primary care visit identifying depression, suicidal thoughts and/or alcohol or substance use disorders, in a single year. The majority of person-hours was devoted to project leadership (35%) and practice coaches (34%), and 36% of costs were for the first three sites.Conclusions: When spread across patients screened in a single year, BHI implementation costs were well within the range for commonly used diagnostic assessments in primary care (eg, laboratory tests). This suggests that implementation costs alone should not be a substantial barrier to population-based BHI. [ABSTRACT FROM AUTHOR]

B This article refers to 'Urinary peptides in heart failure: a link to molecular pathophysiology' by T. He I et al i ., published in this issue on pages 1875-1887. b Proteomic screening of blood and/or urine is gaining prominence as a method to aid discovery of candidate biomarkers to elucidate the molecular basis of disease along with potential applications in clinical diagnosis, risk stratification and treatment decision-making. Urinary peptides in heart failure - the need for care with pees and cues However, whether or not filtration of larger molecular weight peptides out of urine samples (post-sample dilution in SDS containing buffers) also removes bound smaller peptides that could provide extra information remains unknown. [Extracted from the article]

Management strategies designed to conserve coral reefs threatened by climate change need to incorporate knowledge of the spatial distribution of inter‐ and intra‐specific genetic diversity. We characterized patterns of genetic diversity and connectivity using single nucleotide polymorphisms (SNPs) in two reef‐building corals to explore the eco‐evolutionary processes that sustain populations in north‐west Australia. Our sampling focused on the unique reefs of the Kimberley; we collected the broadcast spawning coral Acropora aspera (n = 534) and the brooding coral Isopora brueggemanni (n = 612) across inter‐archipelago (tens to hundreds of kilometres), inter‐reef (kilometres to tens of kilometres) and within‐reef (tens of metres to a few kilometres) scales. Initial analysis of A. aspera identified four highly divergent lineages that were co‐occurring but morphologically similar. Subsequent population analyses focused on the most abundant and widespread lineage, Acropora asp‐c. Although the overall level of geographic subdivision was greater in the brooder than in the spawner, fundamental similarities in patterns of genetic structure were evident. Most notably, limits to gene flow were observed at scales <35 kilometres. Further, we observed four discrete clusters and a semi‐permeable barrier to dispersal that were geographically consistent between species. Finally, sites experiencing bigger tides were more connected to the metapopulation and had greater gene diversity than those experiencing smaller tides. Our data indicate that the inshore reefs of the Kimberley are genetically isolated from neighbouring oceanic bioregions, but occasional dispersal between inshore archipelagos is important for the redistribution of evolutionarily important genetic diversity. Additionally, these results suggest that networks of marine reserves that effectively protect reefs from local pressures should be spaced within a few tens of kilometres to conserve the existing patterns of demographic and genetic connectivity. [ABSTRACT FROM AUTHOR]

Background: Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly‐Xaa‐Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in‐frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease‐associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy. Methods: The patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele‐specific RT‐PCR was performed. Results: This patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9. Conclusion: Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease‐associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1‐related disorders, particularly for those variants that may alter normal pre‐mRNA splicing. [ABSTRACT FROM AUTHOR]

Summary: Leaf decomposition varies widely across temperate forests, shaped by factors like litter quality, climate, soil properties, and decomposers, but forest heterogeneity may mask local tree influences on decomposition and litter‐associated microbiomes. We used a 24‐yr‐old common garden forest to quantify local soil conditioning impacts on decomposition and litter microbiology.We introduced leaf litter bags from 10 tree species (5 arbuscular mycorrhizal; 5 ectomycorrhizal) to soil plots conditioned by all 10 species in a full‐factorial design. After 6 months, we assessed litter mass loss, C/N content, and bacterial and fungal composition. We hypothesized that (1) decomposition and litter‐associated microbiome composition would be primarily shaped by the mycorrhizal type of litter‐producing trees, but (2) modified significantly by underlying soil, based on mycorrhizal type of the conditioning trees.Decomposition and, to a lesser extent, litter‐associated microbiome composition, were primarily influenced by the mycorrhizal type of litter‐producing trees. Interestingly, however, underlying soils had a significant secondary influence, driven mainly by tree species, not mycorrhizal type. This secondary influence was strongest under trees from the Pinaceae.Temperate trees can locally influence underlying soil to alter decomposition and litter‐associated microbiology. Understanding the strength of this effect will help predict biogeochemical responses to forest compositional change. [ABSTRACT FROM AUTHOR]

Key points: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise‐mediated sympathoexcitation.Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise.In the present study, intra‐arterial infusion of ACh or ATP to augment endothelium‐dependent signalling during exercise attenuated α1‐adrenergic vasoconstriction in the contracting muscle of older adults.The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age‐related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. The ability of contracting skeletal muscle to attenuate sympathetic α‐adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults, increasing endothelium‐dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, we tested the hypothesis that increasing endothelium‐dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1, n = 8; Protocol 2, n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra‐arterial infusion of phenylephrine (PE; α1‐agonist) during (i) infusion of an endothelium‐dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium‐dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: −31 ± 3 and ATP: −30 ± 4%). PE‐mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: −30 ± 9; 15% MVC: −33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium‐dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE‐mediated vasoconstriction (ΔFVC: −13 ± 1 and −19 ± 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that, given a sufficient stimulus, endothelium‐dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach for improving sympatholysis and thus tissue blood flow and oxygen delivery in older adults. Key points: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise‐mediated sympathoexcitation.Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise.In the present study, intra‐arterial infusion of ACh or ATP to augment endothelium‐dependent signalling during exercise attenuated α1‐adrenergic vasoconstriction in the contracting muscle of older adults.The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age‐related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background and Purpose: Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro-drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability.Experimental Approach: We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing.Key Results: GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro-drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear.Conclusion and Implications: Using a preclinical screening cascade, we identified a pro-drug for a palindromic molecule with unique pharmacology (miridesap). The pro-drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap. [ABSTRACT FROM AUTHOR]

Consumer confidence and trust, as it relates to the food system, is one of the most sensitive areas within consumers' understanding of food. Surveys have shown that a large majority of people would like to learn more about agriculture and food manufacturing, with young people being among those most eager for more information about where their food comes from. Food‐focused educational resources often go unused due to teachers' lack of familiarity with the subject area, the pressures of standardized testing, and lack of alignment to state content standards. Building on the success of the Hands On Classrooms platform that developed and validated curricula with high adoption rates by teachers and a demonstrated impact on student knowledge and self‐efficacy, a new curriculum on food system and food processing was developed and pilot tested. Two teachers from rural Virginia and Tennessee participated in the study. Both teachers received online professional development prior to implementation. Students were given pretests and posttests to measure (a) what impact does the curriculum have on students' knowledge of food systems and processing and (b) to what extent does the curriculum have an impact on student's self‐reported skills related to these topics? A total of 87 students completed the assessments and showed significant improvements from pretest to posttest on both knowledge (p <.001) and skills (p <.001) related specifically to where food comes from and how it is processed, content that is typically not covered in middle school curriculum. Further research can be undertaken to measure the impact on others in different geographic and socioeconomic areas to provide additional data to validate the program. [ABSTRACT FROM AUTHOR]

Premise: The southern Florida Everglades landscape sustains wetlands of national and international importance. Sawgrass (Cladium jamaicense), the dominant macrophyte in the Everglades, has two phenotypes that vary in size and density between Everglades marl prairies and peat marshes. Marl prairies have recently been hypothesized to be a newly formed habitat developed after European colonization as a result of landscape‐scale hydrologic modifications, implying that sawgrass marl phenotypes developed in response to the marl habitat. We examined whether sawgrass wetland phenotypes are plastic responses to marl and peat soils. Methods: In a common‐mesocosm experiment, seedlings from a single Everglades population were grown outdoors in field‐collected marl or peat soils. Growth and morphology of plants were measured over 14 mo, while soil and leaf total nitrogen, total phosphorus, total carbon, and plant biomass and biomass allocation were determined in a final harvest. Results: Sawgrass plant morphology diverged in marl vs. peat soils, and variations in morphology and density of mesocosm‐grown plants resembled differences seen in sawgrass plants growing in marl and peat habitats in Everglades wetlands. Additionally, sawgrass growing in marl made abundant dauciform roots, while dauciform root production of sawgrass growing in peat was correlated with soil total phosphorus. Conclusions: Sawgrass from a single population grown in marl or peat soils can mimic sawgrass phenotypes associated with marl vs. peat habitats. This plasticity is consistent with the hypothesis that Everglades marl prairies are relatively new habitats that support plant communities assembled after European colonization and subsequent landscape modifications. [ABSTRACT FROM AUTHOR]

Objective: To compare rates of attestation and attrition from the MU program by independent, horizontally integrated, and vertically integrated physicians and to assess whether MU created pressure for independent physicians to join integrated organizations.Data Source/study Setting: Secondary Data from SK&A and Medicare MU Files, 2011-2016. Office-based physicians in the 50 United States and District of Columbia.Study Design: We compared attestation rates among physicians that remained independent or integrated throughout the study period. We then assessed the association between changing integration and MU attestation in multivariate regression models.Principal Findings: Our sample included 291 234 physicians. Forty nine percent of physicians that remained independent throughout the period attested to MU at least once during the program, compared with 70 percent of physicians that remained horizontally or vertically integrated physicians. Only approximately 50 percent of independent physicians that attested between 2011 and 2013 attested in 2015, representing significantly more attrition than we observed among integrated physicians. In multivariate regression models, physicians that joined these organizations were more likely to have attested to MU prior to integrating and this difference increased following integration.Conclusions: These findings point toward a growing digital divide between physicians who remain independent and integrated physicians that may have been exacerbated by the MU program. Targeted public policy, such as new regional extension centers, should be considered to address this disparity. [ABSTRACT FROM AUTHOR]

Objective: Rheumatologic disease patients receiving immunomodulating drugs such as methotrexate (MTX) have increased infection rates. Strongyloides, a global endemic intestinal parasite, can cause significant or fatal disease in immunocompromised patients. The risk of serious Strongyloides infection with MTX dosed for rheumatologic disease is unknown.Methods: We performed a systematic literature review searching EMBASE, Medline and Web of Science databases. All studies reporting humans exposed to MTX and tested for Strongyloides were reviewed. Exclusion criteria were bone marrow transplantation, intrathecal route and MTX exposure completed >1 year prior to clinically apparent Strongyloides disease.Results: After excluding duplicates, 294 articles were reviewed. Of these, 29 cases were described in 27 papers. Twenty cases (69%) had an underlying rheumatologic or dermatologic disease, the rest had a haematologic disease. Hyperinfection or dissemination was found in 59% of cases (52% low-dose MTX; 75% high-dose MTX). Death occurred in 34% of cases (19% low-dose MTX; 75% high-dose MTX, P < 0.01). All eight patients on high-dose MTX received other immunosuppressants. Corticosteroids were taken in 18/21 patients on low-dose MTX. One of the three patients on MTX monotherapy had hyperinfection syndrome. None had disseminated Strongyloides.Conclusions: Serious Strongyloides infection can occur with low-dose MTX particularly when given with other immunosuppression. Global travel and greater awareness of rheumatologic conditions in low- to middle-income countries will increase the exposure of individuals prescribed MTX (with or without corticosteroids) to Strongyloides. Strongyloides screening and treatment should be considered for individuals receiving low-dose MTX therapy, particularly if combined with additional immunosuppression. [ABSTRACT FROM AUTHOR]

Normal median plasma concentrations have been reported at 12 ng/L with a 99th centile upper limit of 87 ng/L and plasma cMyC is measurable in well over 99% of normal subjects using a recently validated sensitive assay.5 Hence cMyC is some fivefold more abundant in plasma than cardiac troponins. The natriuretic peptides, particularly B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), are endorsed by all authoritative guidelines as a highly recommended aid in the diagnosis of acute HF (AHF).1,2 They are reflective of intra-cardiac haemodynamic load. B This article refers to 'Cardiac myosin-binding protein C in the diagnosis and risk stratification of acute heart failure' by N. Kozhuharov I et al i ., published in this issue on pages 716-725. b Biomarkers have become a well-established part of the diagnosis and management of heart failure (HF). [Extracted from the article]

Background and Purpose: The P2X3 receptor is an ATP-gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first-in-class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK-7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK-7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions.Experimental Approach: Whole-cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK-7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation.Key Results: MK-7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration- and state-dependency to wash-on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash-on rate (τ value) for MK-7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK-7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight-bearing discomfort.Conclusions and Implications: MK-7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions. [ABSTRACT FROM AUTHOR]

Premise: At the intersection of ecology and evolutionary biology, community phylogenetics can provide insights into overarching biodiversity patterns, particularly in remote and understudied ecosystems. To understand community assembly of the high alpine flora in the Sawtooth National Forest, USA, we analyzed phylogenetic structure within and between nine summit communities. Methods: We used high‐throughput sequencing to supplement existing data and infer a nearly completely sampled community phylogeny of the alpine vascular flora. We calculated mean nearest taxon distance (MNTD) and mean pairwise distance (MPD) to quantify phylogenetic divergence within summits, and assessed whether maximum elevation explains phylogenetic structure. To evaluate similarities between summits, we quantified phylogenetic turnover, taking into consideration microhabitats (talus vs. meadows). Results: We found different patterns of community phylogenetic structure within the six most species‐rich orders, but across all vascular plants phylogenetic structure was largely not different from random. There was a significant negative correlation between elevation and tree‐wide phylogenetic diversity (MPD) within summits: overdispersion degraded as elevation increased. Between summits, we found high phylogenetic turnover driven by greater niche heterogeneity on summits with alpine meadows. Conclusions: Our results provide further evidence that stochastic processes may also play an important role in the assembly of vascular plant communities in high alpine habitats at regional scales. However, order‐specific patterns suggest that adaptations are still important for assembly of specific sectors of the plant tree of life. Further studies quantifying functional diversity will be important in disentangling the interplay of eco‐evolutionary processes that likely shape broad community phylogenetic patterns in extreme environments. [ABSTRACT FROM AUTHOR]