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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]

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]

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]

Searches for phosphine in Venus' atmosphere have sparked a debate. Cordiner et al. (2022, https://doi.org/10.1029/2022gl101055) analyze spectra from the Stratospheric Observatory For Infrared Astronomy (SOFIA) and infer <0.8 ppb of PH3. We noticed that some spectral artifacts arose from non‐essential calibration‐load signals. By‐passing these signals allows simpler post‐processing and a 5.7σ candidate detection, suggesting ∼3 ppb of PH3 above the clouds. Compiling six phosphine results hints at an inverted abundance trend: decreasing above the clouds but rising again in the mesosphere from some unexplained source. However, no such extra source is needed if phosphine is undergoing destruction by sunlight (photolysis), to a similar degree as on Earth. Low phosphine values/limits are found where the viewed part of the super‐rotating Venusian atmosphere had passed through sunlight, while high values are from views moving into sunlight. We suggest Venusian phosphine is indeed present, and so merits further work on models of its origins. Plain Language Summary: Cordiner et al. (2022, https://doi.org/10.1029/2022gl101055) find no phosphine in Venus' atmosphere, using the airborne SOFIA telescope. By‐passing some instrumental effects, we extract a detection with 5.7σ‐confidence from the same data. We can resolve the tension between high and low PH3 abundance values by noticing that the former are from "mornings" in Venus' atmosphere and the latter from "evenings." Sunlight reduces the amount of phosphine in Earth's atmosphere by an order of magnitude, so similarly on Venus, we might expect lower abundances in data taken when the part of the atmosphere observed has passed through sunlight. If the six available data sets can be reconciled in this way, further modeling of possible sources of PH3 (e.g., volcanic, disequilibrium chemistry, extant life) seem worthwhile. Key Points: We recover Venusian phosphine in SOFIA spectra by reducing contaminating signals; the PH3 abundance is ∼3 part‐per billion (ppb)Six recoveries/limits show PH3 depleting between clouds and mesosphere, which would require an unknown re‐formation process or extra sourceRecoveries and upper limits can instead be reconciled by PH3 photolysis, as high/low abundances correspond to Venusian mornings/evenings [ABSTRACT FROM AUTHOR]

Thermal equilibrium in planetary atmospheres occurs at altitudes where the ion, electron, and neutral temperatures are equal. Thermal equilibrium is postulated to occur in the collision‐dominated ionosphere. This postulated altitude is above the lower boundary of all empirical models of planetary ionospheres. Physics‐based model predictions of the altitude cannot be validated due to a lack of adequate simultaneous observations of temperature profiles. This study presents temperature profiles from simultaneous observations on Atmosphere Explorer–C below 140 km and quiet‐time neutral observations from Thermosphere Ionosphere Mesosphere Energy and Dynamics/Global UltraViolet Imager over Millstone Hill. These are compared with profiles from physics‐based models with a discussion of their respective limitations. We conclude that there does not yet exist a quantitative understanding of the ion, electron, and neutral thermalization processes in low‐altitude planetary ionospheres. Progress on this topic requires an adequate database of simultaneous ion, electron, and neutral temperature profiles in the 110–140 km altitude range. Plain Language Summary: Solar radiation ionizes and heats the neutral atmosphere in the process of creating the ionosphere. Heating begins at the altitude where energy carried by photoelectrons produced by solar extreme ultra violet radiation is not absorbed locally. This is the altitude where the ionosphere and neutral atmosphere are no longer in thermal equilibrium. There are numerous ionospheric models predicting the neutral, ion, and electron temperatures (Tn, Ti, and Te) as a function of altitude. These models predict that, in the absence of other heating mechanisms thermal equilibrium where Ti = Ti = Tn occurs below ∼120 km. Temperatures in this altitude range are used as upper boundary conditions for models attempting to describe energy transfer from the upper atmosphere to the ionosphere. Our study shows that ionospheric models of neutral and plasma temperatures cannot be validated in the region of thermal equilibrium because existing observations are sparse and do not have the precision and/or required spatial and temporal resolution. Progress in understanding energy transfer from the atmosphere to the ionosphere requires validated models of the altitude of thermal equilibrium. Key Points: Thermal equilibrium is postulated to be attained at the lowest altitude heated by photoelectrons but has not been observedQuantitative understanding of thermal equilibrium requires observations that validate modelsThere is an ongoing community need for simultaneous neutral, ion, and electron temperature profiles below 140 km altitude [ABSTRACT FROM AUTHOR]

Experimental exposure of healthy volunteers to the T‐cell dependent neoantigen keyhole limpet hemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to survey the published literature where KLH was used as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies using KLH challenge in humans between January 1, 1994, and April 1, 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co‐administered IMPs, and end points. Of 2421 titles and abstracts screened, 46 met the inclusion criteria, including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T‐cell co‐stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this end point. Two early phase IMP studies (14%) described the response to intradermal re‐challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25‐fold variation: 100–2500 mcg), KLH formulation, and co‐administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue‐level mechanism‐relevant end points afforded by KLH challenge has impaired the translational utility of this paradigm to date. Future standardization, characterization, and methodological development is required to permit tailored, appropriately powered, mechanism‐dependent study design to optimize drug development decisions. [ABSTRACT FROM AUTHOR]

Specifying, assessing, and selecting among candidate statistical models is fundamental to ecological research. Commonly used approaches to model selection are based on predictive scores and include information criteria such as Akaike's information criterion, and cross validation. Based on data splitting, cross validation is particularly versatile because it can be used even when it is not possible to derive a likelihood (e.g., many forms of machine learning) or count parameters precisely (e.g., mixed‐effects models). However, much of the literature on cross validation is technical and spread across statistical journals, making it difficult for ecological analysts to assess and choose among the wide range of options. Here we provide a comprehensive, accessible review that explains important—but often overlooked—technical aspects of cross validation for model selection, such as: bias correction, estimation uncertainty, choice of scores, and selection rules to mitigate overfitting. We synthesize the relevant statistical advances to make recommendations for the choice of cross‐validation technique and we present two ecological case studies to illustrate their application. In most instances, we recommend using exact or approximate leave‐one‐out cross validation to minimize bias, or otherwise k‐fold with bias correction if k < 10. To mitigate overfitting when using cross validation, we recommend calibrated selection via our recently introduced modified one‐standard‐error rule. We advocate for the use of predictive scores in model selection across a range of typical modeling goals, such as exploration, hypothesis testing, and prediction, provided that models are specified in accordance with the stated goal. We also emphasize, as others have done, that inference on parameter estimates is biased if preceded by model selection and instead requires a carefully specified single model or further technical adjustments. [ABSTRACT FROM AUTHOR]

The Lyme disease agent, Borrelia burgdorferi, harbors a significantly reduced genome and relies on the scavenging of critical nutrients from its tick and mammalian hosts for survival. Riboflavin salvage has been shown to be important for B. burgdorferi infection of mice, yet the contributions of riboflavin to B. burgdorferi metabolism and survival in the tick remain unknown. Using a targeted mass spectrometry approach, we confirmed the importance of bb0318, the putative ATPase component of an ABC‐type riboflavin transporter, for riboflavin salvage and the production of FMN and FAD. This analysis further revealed that Δbb0318 B. burgdorferi displayed increased levels of glycerol 3‐phosphate compared to the wild‐type. The glycerol 3‐phosphate dehydrogenase activity of GlpD was found to be FAD‐dependent and the transcription and translation of glpD were significantly decreased in Δbb0318 B. burgdorferi. Finally, gene bb0318 was found to be important for maximal spirochete burden in unfed larvae and essential for survival in feeding ticks. Together, these data demonstrate the importance of riboflavin salvage for B. burgdorferi carbon metabolism and survival in ticks. [ABSTRACT FROM AUTHOR]

Divergent energy acquisition and processing strategies associated with using different microhabitats may allow phenotypes to specialize and coexist at small spatial scales. To understand how ecological specialization affects differentiation in energy acquisition and processing strategies, we examined relationships among digestive physiology, growth, and energetics by performing captive experiments on juveniles of wild coho salmon (Oncorhynchus kisutch) and steelhead trout (O. mykiss) that exploit adjacent habitats along natural low‐to‐high energy flux gradients (i.e., pools versus riffles) in coastal streams. We predicted that: (i) the specialization of steelhead trout to high‐velocity, high‐energy habitats would result in elevated food intake and growth at the cost of lower growth efficiency relative to coho salmon; (ii) the two species would differentiate along a rate‐maximizing (steelhead trout) versus efficiency‐maximizing (coho salmon) axis of digestive strategies matching their ecological lifestyle; and (iii) the higher postprandial metabolic demand (i.e., specific dynamic action, SDA) associated with elevated food intake would occupy a greater fraction of the steelhead trout aerobic budget. Relative to coho salmon, steelhead trout presented a pattern of faster growth and higher food intake but lower growth efficiency, supporting the existence of a major growth versus growth efficiency trade‐off between species. After accounting for differences in ration size between species, steelhead trout also presented higher SDA than coho salmon, but similar intestinal transit time and lower assimilation efficiency. Both species presented similar aerobic budgets since the elevated SDA of steelhead trout was largely compensated by their higher aerobic scope relative to coho salmon. Our results illustrate the key contribution of digestive physiology to the adaptive differentiation of juvenile growth, energetics, and overall performance of taxa with divergent habitat specializations along a natural productivity gradient. [ABSTRACT FROM AUTHOR]

Aims: The influence of human factors on safety in healthcare settings is well established, with targeted interventions reducing risk and enhancing team performance. In experimental and early phase clinical research participant safety is paramount and safeguarded by guidelines, protocolized care and staff training; however, the real‐world interaction and implementation of these risk‐mitigating measures has never been subjected to formal system‐based assessment. Methods: Independent structured observations, systematic review of study documents, and interviews and focus groups were used to collate data on three key tasks undertaken in a clinical research facility (CRF) during a SARS CoV‐2 controlled human infection model (CHIM) study. The Systems Engineering Initiative for Patient Safety (SEIPS) was employed to analyse and categorize findings, and develop recommendations for safety interventions. Results: High levels of team functioning and a clear focus on participant safety were evident throughout the study. Despite this, latent risks in both study‐specific and CRF work systems were identified in all four SEIPS domains (people, environment, tasks and tools). Fourteen actionable recommendations were generated collaboratively. These included inter‐organization and inter‐study standardization, optimized checklists for safety critical tasks, and use of simulation for team training and exploration of work systems. Conclusions: This pioneering application of human factors techniques to analyse work systems during the conduct of research in a CRF revealed risks unidentified by routine review and appraisal, and despite international guideline adherence. SEIPS may aid categorization of system problems and the formulation of recommendations that reduce risk and mitigate potential harm applicable across a trials portfolio. [ABSTRACT FROM AUTHOR]

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

The nucleoside analogue decitabine (or 5-aza-dC) is used to treat several haematological cancers. Upon its triphosphorylation and incorporation into DNA, 5-aza-dC induces covalent DNA methyltransferase 1 DNA–protein crosslinks (DNMT1-DPCs), leading to DNA hypomethylation. However, 5-aza-dC's clinical outcomes vary, and relapse is common. Using genome-scale CRISPR/Cas9 screens, we map factors determining 5-aza-dC sensitivity. Unexpectedly, we find that loss of the dCMP deaminase DCTD causes 5-aza-dC resistance, suggesting that 5-aza-dUMP generation is cytotoxic. Combining results from a subsequent genetic screen in DCTD-deficient cells with the identification of the DNMT1-DPC-proximal proteome, we uncover the ubiquitin and SUMO1 E3 ligase, TOPORS, as a new DPC repair factor. TOPORS is recruited to SUMOylated DNMT1-DPCs and promotes their degradation. Our study suggests that 5-aza-dC-induced DPCs cause cytotoxicity when DPC repair is compromised, while cytotoxicity in wild-type cells arises from perturbed nucleotide metabolism, potentially laying the foundations for future identification of predictive biomarkers for decitabine treatment. Synopsis: The chemotherapeutic decitabine/5-aza-dC induces covalent DNMT1 DNA-protein crosslinks (DPCs), leading to DNMT1 degradation and DNA hypomethylation. This study finds that E3 ligase TOPORS promotes DNMT1-DPC degradation, while deaminase DCTD mediates a DNMT1-independent mode of 5-aza-dC cytotoxicity. The dCMP deaminase DCTD mediates 5-aza-dC cytotoxicity independently of DNA-protein crosslink formation, through the generation of 5-aza-dUMP. The ubiquitin and SUMO1 E3 ligase TOPORS is a novel player in global-genome DPC repair. TOPORS is recruited to SUMOylated DNMT1-DPCs through its SUMO-interaction motifs, whereupon it promotes DNMT1-DPC ubiquitylation and degradation. TOPORS acts in parallel to the E3 ubiquitin ligase RNF4 in mediating DNMT1-DPC tolerance. TOPORS acts in parallel to the ubiquitin ligase RNF4 in degradation of DNMT1-DNA crosslinks, thereby mediating cellular tolerance to these DPCs. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited data on the prevalence and treatment of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. Aim: To estimate the prevalence of at‐risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. Methods: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction‐associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. Results: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co‐existing T2DM and obesity, the prevalence of MASLD, at‐risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). Conclusion: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis is high, posing a significant risk for liver‐related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH‐related fibrosis. [ABSTRACT FROM AUTHOR]

Summary Background Aims Methods Results Conclusions Genetic factors contribute to the risk and severity of metabolic dysfunction‐associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised.To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines.We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration‐controlled transient elastography to assess for advanced fibrosis and cirrhosis.Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis‐4 index (FIB‐4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB‐4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk.Utilising a well‐phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at‐risk populations may improve risk prediction. [ABSTRACT FROM AUTHOR]

Stewartia ovata (cav.) Weatherby, commonly known as mountain stewartia, is an understory tree native to the southeastern United States (U.S.). This relatively rare species occurs in isolated populations in Virginia, Kentucky, Tennessee, North Carolina, South Carolina, Georgia, Alabama, and Mississippi. As a species, S. ovata has largely been overlooked, and limited information is available regarding its ecology, which presents obstacles to conservation efforts. Stewartia ovata has vibrant, large white flowers that bloom in summer with a variety of filament colors, suggesting potential horticultural traits prized by ornamental industry. However, S. ovata is relatively slow growing and, due to long seed dormancy, propagation is challenging with limited success rates. This has created a need to assess the present genetic diversity in S. ovata populations to inform potential conservation and restoration of the species. Here, we employ a genotyping‐by‐sequencing (GBS) approach to characterize the spatial distribution and genetic diversity of S. ovata in the southern Appalachia region of the eastern United States. A total of 4475 single nucleotide polymorphisms (SNPs) were identified across 147 individuals from 11 collection sites. Our results indicate low genetic diversity (He = 0.216), the presence of population structure (K = 2), limited differentiation (FST = 0.039), and high gene flow (Nm = 6.16) between our subpopulations. Principal component analysis corroborated the findings of STRUCTURE, confirming the presence of two distinct S. ovata subpopulations. One subpopulation mainly contains genotypes from the Cumberland Plateau, Tennessee, while the other consists of genotypes present in the Great Smoky Mountain ranges in Tennessee, North Carolina, and portions of Nantahala, Chattahoochee‐Oconee national forests in Georgia, highlighting that elevation likely plays a major role in its distribution. Our results further suggested low inbreeding coefficient (FIS = 0.070), which is expected with an outcrossing tree species. This research further provides necessary insight into extant subpopulations and has generated valuable resources needed for conservation efforts of S. ovata. [ABSTRACT FROM AUTHOR]

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

Objective: Delay in referral for epilepsy surgery of patients with drug‐resistant epilepsy (DRE) is associated with decreased quality of life, worse surgical outcomes, and increased risk of sudden unexplained death in epilepsy (SUDEP). Understanding the potential causes of delays in referral and treatment is crucial for optimizing the referral and treatment process. We evaluated the treatment intervals, demographics, and clinical characteristics of patients referred for surgical evaluation at our level 4 epilepsy center in the U.S. Intermountain West. Methods: We retrospectively reviewed the records of patients who underwent surgery for DRE between 2012 and 2022. Data collected included patient demographics, DRE diagnosis date, clinical characteristics, insurance status, distance from epilepsy center, date of surgical evaluation, surgical procedure, and intervals between different stages of evaluation. Results: Within our cohort of 185 patients with epilepsy (99 female, 53.5%), the mean ± standard deviation (SD) age at surgery was 38.4 ± 11.9 years. In this cohort, 95.7% of patients had received definitive epilepsy surgery (most frequently neuromodulation procedures) and 4.3% had participated in phase 2 intracranial monitoring but had not yet received definitive surgery. The median (1st–3rd quartile) intervals observed were 10.1 (3.8–21.5) years from epilepsy diagnosis to DRE diagnosis, 16.7 (6.5–28.4) years from epilepsy diagnosis to surgery, and 1.4 (0.6–4.0) years from DRE diagnosis to surgery. We observed significantly shorter median times from epilepsy diagnosis to DRE diagnosis (p <.01) and epilepsy diagnosis to surgery (p <.05) in patients who traveled further for treatment. Patients with public health insurance had a significantly longer time from DRE diagnosis to surgery (p <.001). Significance: Both shorter distance traveled to our epilepsy center and public health insurance were predictive of delays in diagnosis and treatment intervals. Timely referral of patients with DRE to specialized epilepsy centers for surgery evaluation is crucial, and identifying key factors that may delay referral is paramount to optimizing surgical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Patients face a myriad of personal and system‐based challenges in accessing breast cancer care, but less is known about access as expressed and experienced by patients themselves. The objective of this qualitative study was to further explore the breadth of issues related to access from the perspective of patients with breast cancer across their care journey. Methods: Twelve women participated in 1‐h semi‐structured interviews and 48 women participated in 2‐h focus groups at six oncology practices in 2018. Grounded theory was used to analyze the data. Results: Six primary themes emerged concerning access to care: information, psychosocial support, health insurance, financial resources, timeliness, and emotions. Conclusions: This study identified six core dimensions of access to care. Access encompassed not only gaining entrée to care services—in the traditional sense of access—but also the continuing support needed to effectively use those services throughout the cancer care journey. Future strategies aimed at improving access to breast cancer care should attend to these ongoing patient‐centric and system‐based issues which are mostly amenable to change. [ABSTRACT FROM AUTHOR]

Summary: Vulnerability to xylem cavitation is a strong predictor of drought‐induced damage in forest communities. However, biotic features of the community itself can influence water availability at the individual tree‐level, thereby modifying patterns of drought damage.Using an experimental forest in Tasmania, Australia, we determined the vulnerability to cavitation (leaf P50) of four tree species and assessed the drought‐induced canopy damage of 2944 6‐yr‐old trees after an extreme natural drought episode. We examined how individual damage was related to their size and the density and species identity of neighbouring trees.The two co‐occurring dominant tree species, Eucalyptus delegatensis and Eucalyptus regnans, were the most vulnerable to drought‐induced xylem cavitation and both species suffered significantly greater damage than neighbouring, subdominant species Pomaderris apetala and Acacia dealbata. While the two eucalypts had similar leaf P50 values, E. delegatensis suffered significantly greater damage, which was strongly related to the density of neighbouring P. apetala. Damage in E. regnans was less impacted by neighbouring plants and smaller trees of both eucalypts sustained significantly more damage than larger trees.Our findings demonstrate that natural drought damage is influenced by individual plant physiology as well as the composition, physiology and density of the surrounding stand. [ABSTRACT FROM AUTHOR]

Snake venom is produced, transported and delivered by the sophisticated venom delivery system (VDS). When snakes bite, the venom travels from the venom gland through the venom duct into needle‐like fangs that inject it into their prey. To counteract breakages, fangs are continuously replaced throughout life. Currently, the anatomy of the connection between the duct and the fang has not been described, and the mechanism by which the duct is reconnected to the replacement fang has not been identified. We examined the VDS in 3D in representative species from two families and one subfamily (Elapidae, Viperidae, Atractaspidinae) using contrast‐enhanced microCT (diceCT), followed by dissection and histology. We observed that the venom duct bifurcates immediately anterior to the fangs so that both the original and replacement fangs are separately connected and functional in delivering venom. When a fang is absent, the canal leading to the empty position is temporarily closed. We found that elapid snakes have a crescent‐shaped venom reservoir where venom likely pools before it enters the fang. These findings form the final piece of the puzzle of VDS anatomy in front‐fanged venomous snakes. Additionally, they provide further evidence for independent evolution of the VDS in these three snake taxa. [ABSTRACT FROM AUTHOR]