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OBJECTIVES: Noninvasive technology may assist the emergency department (ED) physician in determining the hemodynamic status in critically ill patients. The objective of our study was to show that ED physicians can accurately measure cardiac index (CI) by performing a bedside focused cardiac ultrasound examination. METHODS: A convenience sample of adult subjects were prospectively enrolled. Cardiac index, left ventricular outflow tract (LVOT) diameter, velocity time integral (VTI), stroke volume index, and heart rate were obtained by trained ED physicians and a certified cardiac sonographer. The primary outcome was percent of optimal LVOT diameter and VTI measurements as verified by an expert cardiologist. RESULTS: One hundred patients were enrolled, with obtainable CI measurements in 97 patients. Cardiac index, LVOT diameter, VTI, stroke volume index, and heart rate measurements by ED physician were 2.42 ± 0.70 L min(-1) m(-2), 2.07 ± 0.22 cm, 18.30 ± 3.71 cm, 32.34 ± 7.92 mL beat(-1) m(-2), and 75.32 ± 13.45 beats/min, respectively. Measurements of LVOT diameter by ED physicians and sonographer were optimal in 90.0% (95% confidence interval, 82.6%-94.5) and 91.3% (73.2%-97.6%) of patients, respectively. Optimal VTI measurements were obtained in 78.4% (69.2%-85.4%) and 78.3% (58.1%-90.3%) of patients, respectively. In 23 patients, the correlation (r) for CI between ED physician and sonographer was 0.82 (0.60-0.92), with bias and limits of agreement of -0.11 (-1.06 to 0.83) L min(-1) m(-2) and percent difference of 12.4% ± 10.1%. CONCLUSIONS: Emergency department ED physicians can accurately measure CI using standard bedside ultrasound. A focused ultrasound cardiac examination to derive CI has potential use in the management of critical ill patients in the ED. [ABSTRACT FROM AUTHOR]

Objective: The complexity of interactions between genes and the environment is a major challenge for type 1 diabetes studies. Nuclear chromatin is the interface between genetics and environment and the principal carrier of epigenetic information. Because histone tail modifications in chromatin are linked to gene transcription, we hypothesized that histone methylation patterns in cells from type 1 diabetic patients can provide novel epigenetic insights into type 1 diabetes and its complications.Research Design and Methods: We used chromatin immunoprecipitation (ChIP) linked to microarray (ChIP-chip) approach to compare genome-wide histone H3 lysine 9 dimethylation (H3K9me2) patterns in blood lymphocytes and monocytes from type 1 diabetic patients versus healthy control subjects. Bioinformatics evaluation of methylated candidates was performed by Ingenuity Pathway Analysis (IPA) tools.Results: A subset of genes in the type 1 diabetic cohort showed significant increase in H3K9me2 in lymphocytes but not in monocytes. CLTA4, a type 1 diabetes susceptibility gene, was one of the candidates displaying increased promoter H3K9me2 in type 1 diabetes. IPA identified two high-scoring networks that encompassed genes showing altered H3K9me2. Many of them were associated with autoimmune and inflammation-related pathways, such as transforming growth factor-beta, nuclear factor-kappaB, p38 mitogen-activated protein kinase, toll-like receptor, and interleukin-6. IPA also revealed biological relationships between these networks and known type 1 diabetes candidate genes.Conclusions: The concerted and synergistic alteration of histone methylation within the identified network in lymphocytes might have an effect on the etiology of type 1 diabetes and its complications. These studies provide evidence of a novel association between type 1 diabetes and altered histone methylation of key genes that are components of type 1 diabetes-related biological pathways and also a new understanding of the pathology of type 1 diabetes. [ABSTRACT FROM AUTHOR]

RATIONALE: Multiple tests are required for the management of lung cancer. OBJECTIVES: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was evaluated as a single test for the diagnosis and staging (thoracic and extrathoracic) of lung cancer. METHODS: Consecutive subjects with computed tomography (CT) findings of a lung mass were enrolled for EUS and results were compared with those from CT and positron emission tomography scans. RESULTS: Of 113 subjects with lung cancer, EUS was performed as a first test (after CT scan) for diagnosis in 93 (82%) of them. EUS-FNA established tissue diagnosis in 70% of cases. EUS-FNA, CT, and positron emission tomography detected metastases to the mediastinal lymph nodes with accuracies of 93, 81, and 83%, respectively. EUS-FNA was significantly better than CT at detecting distant metastases (accuracies of 97 and 89%, respectively; p = 0.02). Metastases to lymph nodes at the celiac axis (CLNs) were observed in 11% of cases. The diagnostic yields of EUS-FNA and CT for detection of metastases to the CLNs were 100 and 50%, respectively (p < 0.05). EUS was able to detect small metastases (less than 1 cm) often missed by CT. Metastasis to the CLNs was a predictor of poor survival of subjects with non-small cell lung cancer, irrespective of the size of the CLNs. Of 44 cases with resectable tumor on CT scan, EUS-FNA avoided thoracotomy in 14% of cases. CONCLUSIONS: EUS-FNA as a first test (after CT) has high diagnostic yield and accuracy for detecting lung cancer metastases to the mediastinum and distant sites. Metastasis to the CLNs is associated with poor prognosis. EUS-FNA is able to detect occult metastasis to the CLNs and thus avoids thoracotomy. [ABSTRACT FROM AUTHOR]

A number of factors complicate the diagnosis of asbestos-related pulmonary diseases. Most persons who have had heavy exposure to asbestos are now aged at least 65 years and, therefore, are more likely to have other respiratory problems, such as chronic obstructive pulmonary disease, that may be difficult to differentiate from asbestosis. An accurate assessment of exposure history is particularly challenging because of poor recall of events by patients and because critical variables, such as fiber type, size, and length, can be difficult to evaluate. High-resolution CT (HRCT) has better sensitivity and specificity for asbestos-related pleural disease and neoplasms than does chest radiography. However, HRCT findings in patients with asbestosis are relatively nonspecific. Bronchoalveolar lavage and lung biopsy can provide definitive information about the extent of asbestos exposure. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between sonographic features of placenta previa and vaginal bleeding (VB)., Study Design: Retrospective cohort study of women with placenta previa identified on ultrasound between 16 0/7 and 27 6/7 weeks gestation. Placental distance past the cervical os (DPO), placental thickness, edge angle, and cervical length (CL) were measured. The primary outcome was any VB and the secondary outcome was VB requiring delivery. Median values of the sonographic features were compared for each of the outcomes using the Mann-Whitney U test. Receiver operating characteristic curves were used to compare the predictive value of sonographic variables markers and to determine optimal cut points for each measurement. Logistic regression was used to estimate the association between each measure and the outcomes while controlling for confounders., Results: Of 149 women with placenta previa, 37% had VB and 15% had VB requiring delivery. Women with VB requiring delivery had significantly more episodes of VB than those who did not require delivery for VB (1.5, interquartile range [IQR] [1-3] vs 1.0 [1-5]; p  = 0.001). In univariate analysis, women with VB had decreased CL (3.9 vs. 4.2 cm; p  < 0.01) compared with those without. Women with VB requiring delivery had increased DPO (2.6 cm IQR [1.7-3.3] vs. 1.5 cm [1.1-2.4], p  = 0.01) compared with those without. After adjusting for confounders, only CL < 4 cm remained independently associated with increased risk of VB (adjusted odds ratio: 2.27, 95% confidence interval [1.12-4.58], p  = 0.01). None of the measures were predictive of either outcome (area under the curve < 0.65)., Conclusion: Decreased CL may be associated with risk of VB in placenta previa., Key Points: · Placenta previa is associated with VB.. · Sonographic markers of placenta previa are associated with VB.. · CL is associated with VB in placenta previa, whereas placental DPO is associated with higher rates of bleeding leading to delivery.., Competing Interests: None declared., (Thieme. All rights reserved.)

Global climate change and land use change underlie a need to develop new crop breeding strategies, and crop wild relatives (CWR) have become an important potential source of new genetic material to improve breeding efforts. Many recent approaches assume adaptive trait variation increases towards the relative environmental extremes of a species range, potentially missing valuable trait variation in more moderate or typical climates. Here, we leveraged distinct genotypes of wild chickpea (Cicer reticulatum) that differ in their relative climates from moderate to more extreme and perform targeted assessments of drought and heat tolerance. We found significance variation in ecophysiological function and stress tolerance between genotypes but contrary to expectations and current paradigms, it was individuals from more moderate climates that exhibited greater capacity for stress tolerance than individuals from warmer and drier climates. These results indicate that wild germplasm collection efforts to identify adaptive variation should include the full range of environmental conditions and habitats instead of only environmental extremes, and that doing so may significantly enhance the success of breeding programs broadly., (© 2024. The Author(s).)

Tradeoffs between the energetic benefits and costs of traits can shape species and trait distributions along environmental gradients. Here we test predictions based on such tradeoffs using survival, growth, and 50 photosynthetic, hydraulic, and allocational traits of ten Eucalyptus species grown in four common gardens along an 8-fold gradient in precipitation/pan evaporation (P/E p ) in Victoria, Australia. Phylogenetically structured tests show that most trait-environment relationships accord qualitatively with theory. Most traits appear adaptive across species within gardens (indicating fixed genetic differences) and within species across gardens (indicating plasticity). However, species from moister climates have lower stomatal conductance than others grown under the same conditions. Responses in stomatal conductance and five related traits appear to reflect greater mesophyll photosynthetic sensitivity of mesic species to lower leaf water potential. Our data support adaptive cross-over, with realized height growth of most species exceeding that of others in climates they dominate. Our findings show that pervasive physiological, hydraulic, and allocational adaptations shape the distributions of dominant Eucalyptus species along a subcontinental climatic moisture gradient, driven by rapid divergence in species P/E p and associated adaptations., (© 2023. The Author(s).)

Purpose: Attentional control theory (ACT) posits that elevated anxiety increases the probability of re-allocating cognitive resources needed to complete a task to processing anxiety-related stimuli. This process impairs processing efficiency and can lead to reduced performance effectiveness. Science, technology, engineering, and math (STEM) students frequently experience anxiety about their coursework, which can interfere with learning and performance and negatively impact student retention and graduation rates. The objective of this study was to extend the ACT framework to investigate the neurobiological associations between science and math anxiety and cognitive performance among 123 physics undergraduate students., Procedures: Latent profile analysis (LPA) identified four profiles of science and math anxiety among STEM students, including two profiles that represented the majority of the sample (Low Science and Math Anxiety; 59.3% and High Math Anxiety; 21.9%) and two additional profiles that were not well represented (High Science and Math Anxiety; 6.5% and High Science Anxiety; 4.1%). Students underwent a functional magnetic resonance imaging (fMRI) session in which they performed two tasks involving physics cognition: the Force Concept Inventory (FCI) task and the Physics Knowledge (PK) task., Findings: No significant differences were observed in FCI or PK task performance between High Math Anxiety and Low Science and Math Anxiety students. During the three phases of the FCI task, we found no significant brain connectivity differences during scenario and question presentation, yet we observed significant differences during answer selection within and between the dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN). Further, we found significant group differences during the PK task were limited to the DAN, including DAN-VAN and within-DAN connectivity., Conclusions: These results highlight the different cognitive processes required for physics conceptual reasoning compared to physics knowledge retrieval, provide new insight into the underlying brain dynamics associated with anxiety and physics cognition, and confirm the relevance of ACT theory for science and math anxiety., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Despite the recognized importance of hydraulic capacitance as a mechanism used by plants to maintain hydraulic functioning during high transpiration, characterizing the dynamics of capacitance remains a challenge., Methods: We used a novel 'two-balance method' to investigate relationships between stem rehydration kinetics and other hydraulic traits in multiple tree species, and we developed a model to explore stem rehydration kinetics further., Key Results: We found that: (1) rehydration time constants and the amount of water uptake occurring during rehydration differed significantly across species; (2) time constants did not change with declining water potential (Ψ), while water uptake increased at lower Ψ in some species; (3) longer time constants were associated with lower wood density, higher capacitance and less negative stem pressures causing 50 % loss of hydraulic conductivity (P50); (4) greater water uptake occurred in stems with lower wood density and less negative P50 values; and (5) the model could estimate the total hydraulic resistance of the rehydration path, which cannot be measured directly., Conclusions: Overall, the two-balance method can be used to examine rehydration dynamics quickly and thoroughly in detached woody stems. This method has the potential to improve our understanding of how capacitance functions across tree species, which is an often-overlooked component of whole-plant hydraulics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Conifers inhabit some of the most challenging landscapes where multiple abiotic stressors (e.g., aridity, freezing temperatures) often co-occur. Physiological tolerance to multiple stressors ('poly-tolerance') is thought to be rare because exposure to one stress generally limits responses to another through functional trade-offs. However, the capacity to exhibit poly-tolerance may be greater when combined abiotic stressors have similar physiological impacts, such as the disruption of hydraulic function imposed by drought or freezing. Here, we reviewed empirical data in light of theoretical expectations for conifer adaptations to drought and freeze-thaw cycles with particular attention to hydraulic traits of the stem and leaf. Additionally, we examined the commonality and spatial distribution of poly-stress along indices of these combined stressors. We found that locations with the highest values of our poly-stress index (PSi) are characterized by moderate drought and moderate freeze-thaw, and most of the global conifer distribution occupies areas of moderate poly-stress. Among traits examined, we found diverse responses to the stressors. Turgor loss point did not correlate with freeze-thaw or drought stress individually, but did with the PSi, albeit inverse to what was hypothesized. Leaf mass per area was more strongly linked with drought stress than the poly-stress and not at all with freeze-thaw stress. In stems, the water potential causing 50% loss of hydraulic conductivity became more negative with increasing drought stress and poly-stress but did not correlate with freeze-thaw stress. For these traits, we identified a striking lack of coverage for substantial portions of species ranges, particularly at the upper boundaries of their respective PSis, demonstrating a critical gap in our understanding of trait prevalence and plasticity along these stress gradients. Future research should investigate traits that confer tolerance to both freeze-thaw and drought stress in a wide range of species across broad geographic scales., (© The Author(s) 2022. Published by Oxford University Press.)

Neuroscientists have sought to identify the underlying neural systems supporting social processing that allow interaction and communication, forming social relationships, and navigating the social world. Through the use of NIMH's Research Domain Criteria (RDoC) framework, we evaluated consensus among studies that examined brain activity during social tasks to elucidate regions comprising the "social brain". We examined convergence across tasks corresponding to the four RDoC social constructs, including Affiliation and Attachment, Social Communication, Perception and Understanding of Self, and Perception and Understanding of Others. We performed a series of coordinate-based meta-analyses using the activation likelihood estimate (ALE) method. Meta-analysis was performed on whole-brain coordinates reported from 864 fMRI contrasts using the NiMARE Python package, revealing convergence in medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, temporoparietal junction, bilateral insula, amygdala, fusiform gyrus, precuneus, and thalamus. Additionally, four separate RDoC-based meta-analyses revealed differential convergence associated with the four social constructs. These outcomes highlight the neural support underlying these social constructs and inform future research on alterations among neurotypical and atypical populations., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: An individual plant consists of different-sized shoots, each of which consists of different-sized leaves. To predict plant-level physiological responses from the responses of individual leaves, modelling this within-shoot leaf size variation is necessary. Within-plant leaf trait variation has been well investigated in canopy photosynthesis models but less so in plant allometry. Therefore, integration of these two different approaches is needed., Methods: We focused on an established leaf-level relationship that the area of an individual leaf lamina is proportional to the product of its length and width. The geometric interpretation of this equation is that different-sized leaf laminas from a single species share the same basic form. Based on this shared basic form, we synthesized a new length-times-width equation predicting total shoot leaf area from the collective dimensions of leaves that comprise a shoot. Furthermore, we showed that several previously established empirical relationships, including the allometric relationships between total shoot leaf area, maximum individual leaf length within the shoot and total leaf number of the shoot, can be unified under the same geometric argument. We tested the model predictions using five species, all of which have simple leaves, selected from diverse taxa (Magnoliids, monocots and eudicots) and from different growth forms (trees, erect herbs and rosette herbs)., Key Results: For all five species, the length-times-width equation explained within-species variation of total leaf area of a shoot with high accuracy (R2 > 0.994). These strong relationships existed despite leaf dimensions scaling very differently between species. We also found good support for all derived predictions from the model (R2 > 0.85)., Conclusions: Our model can be incorporated to improve previous models of allometry that do not consider within-shoot size variation of individual leaves, providing a cross-scale linkage between individual leaf-size variation and shoot-size variation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company.)

The isohydric-anisohydric continuum describes the relative stringency of stomatal control of leaf water potential (ψ leaf ) during drought. Hydroscape area (HA)-the water potential landscape over which stomata regulate ψ leaf -has emerged as a useful metric of the iso/anisohydric continuum because it is strongly linked to several hydraulic, photosynthetic and structural traits. Previous research on HA focused on broad ecological patterns involving several plant clades. Here we investigate the relationships between HA and climatic conditions and functional traits across ecologically diverse but closely related species while accounting for phylogeny. Across a macroclimatic moisture gradient, defined by the ratio of mean annual precipitation to mean annual pan evaporation (P/E p ), HA decreased with increased P/E p across 10 Eucalyptus species. Greater anisohydry reflects lower turgor loss points and greater hydraulic safety, mirroring global patterns. Larger HA coincides with mesophyll photosynthetic capacity that is more sensitive to ψ leaf . Hydroscapes exhibit little plasticity in response to variation in water supply, and the extent of plasticity does not vary with P/E p of native habitats. These findings strengthen the case that HA is a useful metric for characterizing drought tolerance and water-status regulation., (© 2022 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases, but requires the incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface-modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2 kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 μm diameter) surface-modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies. We found that, compared to MP surface-modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 μL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice with minimal lung inflammation. Thus, surface modification of ~1 μm biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.

Fluorescently-labeled solute-binding proteins that alter their fluorescence output in response to ligand binding have been utilized as biosensors for a variety of applications. Coupling protein ligand binding to altered fluorescence output often requires trial and error-based testing of both multiple labeling positions and fluorophores to produce a functional biosensor with the desired properties. This approach is laborious and can lead to reduced ligand binding affinity or altered ligand specificity. Here we report the Computational Identification of Non-disruptive Conjugation sites (CINC) for streamlined identification of fluorophore conjugation sites. By exploiting the structural dynamics properties of proteins, CINC identifies positions where conjugation of a fluorophore results in a fluorescence change upon ligand binding without disrupting protein function. We show that a CINC-developed maltooligosaccharide (MOS)-detecting biosensor is capable of rapid (k on  = 20 μM -1 s -1 ), sensitive (sub-μM K D ) and selective MOS detection. The MOS-detecting biosensor is modular with respect to the spectroscopic properties and demonstrates portability to detecting MOS released via α-amylase-catalyzed depolymerization of starch using both a stopped-flow and a microplate reader assay. Our MOS-detecting biosensor represents a first-in-class probe whose design was guided by changes in localized dynamics of individual amino acid positions, supporting expansion of the CINC pipeline as an indispensable tool for a wide range of protein engineering applications., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fluorescently labeled, solute-binding proteins that change their fluorescent output in response to ligand binding are frequently used as biosensors for a wide range of applications. We have previously developed a "Computational Identification of Non-disruptive Conjugation sites" (CINC) approach, an in silico pipeline utilizing molecular dynamics simulations for the rapid design and construction of novel protein-fluorophore conjugate-type biosensors. Here, we report an improved in silico scoring algorithm for use in CINC and its use in the construction of an oligogalacturonide-detecting biosensor set. Using both 4,5-unsaturated and saturated oligogalacturonides, we demonstrate that signal transmission from the ligand-binding pocket of the starting protein scaffold to the CINC-selected reporter positions is effective for multiple different ligands. The utility of an oligogalacturonide-detecting biosensor is shown in Carbohydrate Active Enzyme (CAZyme) activity assays, where the biosensor is used to follow product release upon polygalacturonic acid (PGA) depolymerization in real time. The oligogalacturonide-detecting biosensor set represents a novel enabling tool integral to our rapidly expanding platform for biosensor-based carbohydrate detection, and moving forward, the CINC pipeline will continue to enable the rational design of biomolecular tools to detect additional chemically distinct oligosaccharides and other solutes.

Introduction: The ability to appropriately seek help is a key skill for medical students transitioning to residency. We designed a simulation activity for senior medical students and became interested in studying help calling behaviors and attitudes., Methods: We collected quantitative data regarding help calling for 2 simulation cases and qualitative data using a survey. We undertook a structured thematic analysis based on grounded theory methodology. We identified and compared groups who did and did not call for help., Results: One hundred thirty-four students participated and 122 (91%) completed an evaluation. More students called for help without prompting in the second case (34/134, 25% in first case; 110/134, 82% in second case, P < 0.001). Most students did not call for help in the first case but called in the second case (81, 60%). Our qualitative analysis identified 5 themes: (1) students seek to avoid shame and burdening their team, (2) prior institutional simulation and testing experience may imprint help calling behaviors, (3) students view help calling primarily through an individual lens, (4) students overestimate the complexity of the help calling process, and (5) the simulation environment and intentional experimentation make it difficult to observe natural behavior. When compared with help callers, more non-help callers had phrases coded as "perception of expectations" (37% vs. 10%, P = 0.03)., Conclusions: Learners participating in simulation exercises designed to promote help-calling behaviors face training-based barriers related to shame and the desire for autonomy and simulation-based challenges related to assessment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Society for Simulation in Healthcare.)

Photosynthetic sensitivity to drought is a fundamental constraint on land-plant evolution and ecosystem function. However, little is known about how the sensitivity of photosynthesis to nonstomatal limitations varies among species in the context of phylogenetic relationships. Using saplings of 10 Eucalyptus species, we measured maximum CO 2 -saturated photosynthesis using A-c i curves at several different leaf water potentials (ψ leaf ) to quantify mesophyll photosynthetic sensitivity to ψ leaf (MPS), a measure of how rapidly nonstomatal limitations to carbon uptake increase with declining ψ leaf . MPS was compared to the macroclimatic moisture availability of the species' native habitats, while accounting for phylogenetic relationships. We found that species native to mesic habitats have greater MPS but higher maximum photosynthetic rates during non-water-stressed conditions, revealing a trade-off between maximum photosynthesis and drought sensitivity. Species with lower turgor loss points have lower MPS, indicating coordination among photosynthetic and water-relations traits. By accounting for phylogenetic relationships among closely related species, we provide the first compelling evidence that MPS in Eucalyptus evolved in an adaptive fashion with climatically determined moisture availability, opening the way for further study of this poorly explored dimension of plant adaptation to drought., (© 2021 The Authors New Phytologist © 2021 New Phytologist Foundation.)

Purpose: Hospitalizations during cancer treatment are costly, can impair quality of life, and negatively affect therapy completion. Our objective was to identify risk factors for unplanned hospitalization among older adults receiving chemotherapy., Methods: This is a secondary analysis of a multisite cohort study (N = 750) of patients ≥ 65 years of age evaluated with a geriatric assessment (GA) to predict chemotherapy toxicity. The primary outcome of this analysis was unplanned hospitalizations during treatment; the secondary outcome was length of stay (LOS) of the first hospitalization. Independent variables included pretreatment GA measures, laboratory values, cancer type and stage, and treatment intensity characteristics. We used logistic regression to estimate the odds of hospitalization and generalized linear models for LOS in multivariable analyses., Results: The sample median age was 72 years (range, 65-94 years); 59% had stage IV disease. At least one unplanned hospitalization occurred in 193 patients (25.7%) during receipt of chemotherapy. In multivariable analyses controlling for cancer type, the following baseline characteristics were significantly associated with increased odds of hospitalization: needing help bathing or dressing (odds ratio [OR], 1.8; 95% CI, 1.0 to 3.1), polypharmacy (≥ 5 meds) (OR, 1.6; 95% CI, 1.1 to 2.4), more comorbid conditions (OR, 1.1; 95% CI, 1.0 to 1.3), availability of someone to take them to the doctor (OR, 2.0; 95% CI, 1.0 to 4.1), CrCl < 60 mL/min (OR, 1.7; 95% CI, 1.1 to 2.4), and albumin < 3.5 g/dL (OR, 1.8; 95% CI, 1.2 to 2.8). In multivariable analyses, older age, self-reported presence of liver or kidney disease, living alone and depressive symptoms were associated with longer LOS., Conclusion: Readily available GA variables and laboratory data, but not age, were associated with unplanned hospitalizations among older adults receiving chemotherapy. If validated, these data can inform prediction models and the design of interventions to decrease unplanned hospitalizations., Competing Interests: Amanda Nickles FaderHonoraria: Ethicon, Mersana, Intuitive SurgicalConsulting or Advisory Role: Merck Christian MeyerConsulting or Advisory Role: BayerSpeakers' Bureau: NovartisTravel, Accommodations, Expenses: Plexxikon, LillyOther Relationship: UpToDate Stephanie GaillardConsulting or Advisory Role: Immunogen, AstraZeneca, Sermonix Pharmaceuticals, RigelResearch Funding: PharmaMar, Genentech/Roche, Iovance Biotherapeutics, Abbvie, AstraZeneca, Pfizer, TesaroPatents, Royalties, Other Intellectual Property: Sermonix PharmaceuticalsNo other potential conflicts of interest were reported.

Wild-type KRAS (KRAS WT ) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRAS WT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.

Trade-offs between photosynthesis and the costs of resource capture inform economic strategies of plants across environmental gradients and result in predictable variation in leaf traits. However, understudied functional groups like hemiparasites that involve dramatically different strategies for resource capture may have traits that deviate from expectations. We measured leaf traits related to gas exchange in mistletoes and their eucalypt hosts along a climatic gradient in relative moisture supply, measured as the ratio of precipitation to pan evaporation (P/E p ), in Victoria, Australia. We compared traits for mistletoes vs. hosts as functions of relative moisture supply and examined trait-trait correlations in both groups. Eucalypt leaf traits responded strongly to decreasing P/E p , consistent with economic theory. Leaf area and specific leaf area (SLA) decreased along the P/E p gradient, while C:N ratio, leaf thickness, N per area, and δ 13 C all increased. Mistletoes responded overall less strongly to P/E p based on multivariate analyses; individual traits sometimes shifted in parallel with those of hosts, but SLA, leaf thickness, and N per area showed no significant change across the gradient. For mistletoes, leaf thickness was inversely related to leaf dry matter content (LDMC), with no relationship between SLA and mass-based N. In mistletoes, reduced costs of transpiration (reflecting their lack of roots) and abundant succulent leaf tissue help account for observed differences from their eucalypt hosts. Trait-based analysis of atypical functional types such as mistletoes help refine hypotheses based on plant economics and specialized adaptations to resource limitation.

Objective: This study aimed to compare the risk of recurrent spontaneous preterm birth (sPTB), as well as cerclage efficacy, between groups stratified by phenotype of the index sPTB., Study Design: This is a retrospective cohort study of women with a history of sPTB. Included were women with a history of singleton sPTB who received progesterone in a subsequent pregnancy. Multifetal gestations and abdominal cerclage were excluded. Exposure groups were based upon the presenting symptom that preceded their first sPTB and included painless cervical dilation (PCD), preterm premature rupture of membranes (PPROM), and painful dilation (preterm labor [PTL]). Primary outcome was delivery <34 weeks in a subsequent pregnancy. Secondary outcomes included delivery <28 and <37 weeks. Rates were compared using the Chi-square test. Multivariable Poisson regression was used to adjust for confounders., Results: A total of 723 women were included. A total of 114 (16%) presented with PCD, 305 (42%) with PPROM, and 304 (42%) with PTL in their first sPTB. Cerclage in subsequent pregnancy was highest in the PCD group (42%) when compared with the PPROM (16%) and PTL (12%) groups. Rates of sPTB <34 and 37 weeks were similar among the groups. After adjusting for confounders, PCD was found to significantly increase the risk of recurrent sPTB <28 weeks (incidence rate ratio: 3.46 [1.09-11.0]; p  = 0.04). Of the 121 women who underwent cerclage, there were no significant differences in rates of sPTB between the clinical presentation groups., Conclusion: PCD as a specific phenotype of sPTB impacts recurrence of delivery before 28 weeks, but not at later gestational ages. In contrast, there was no significant association between clinical presentation of index sPTB and gestational latency in women who also underwent cerclage placement in a subsequent pregnancy. Our data suggest that clinical presentation is important with regards to recurrence of early sPTB, but not sPTB at later gestational ages., Key Points: · Phenotype is critical to understanding PTB.. · Phenotype is associated with recurrent PTB.. · Painless dilation is associated with recurrent PTB.., Competing Interests: None declared., (Thieme. All rights reserved.)

The intensity of extreme heat and drought events has drastically risen in recent decades and will likely continue throughout the century. Northern forests have already seen increases in tree mortality and a lack of new recruitment, which is partially attributed to these extreme events. Boreal species, such as paper birch (Betula papyrifera) and white spruce (Picea glauca), appear to be more sensitive to these changes than lower-latitude species. Our objectives were to investigate the effects of repeated heatwaves and drought on young paper birch and white spruce trees by examining (i) responses in leaf gas exchange and plant growth and (ii) thermal acclimation of photosynthetic and respiratory traits to compare ecophysiological responses of two co-occurring, yet functionally dissimilar species. To address these objectives, we subjected greenhouse-grown seedlings to two consecutive summers of three 8-day long, +10 °C heatwaves in elevated atmospheric CO2 conditions with and without water restriction. The data show that heatwave stress reduced net photosynthesis, stomatal conductance and growth-more severely so when combined with drought. Acclimation of both photosynthesis and respiration did not occur in either species. The combination of heat and drought stress had a similar total effect on both species, but each species adjusted traits differently to the combined stress. Birch experienced greater declines in gas exchange across both years and showed moderate respiratory but not photosynthetic acclimation to heatwaves. In spruce, heatwave stress reduced the increase in basal area in both experimental years and had a minor effect on photosynthetic acclimation. The data suggest these species lack the ability to physiologically adjust to extreme heat events, which may limit their future distributions, thereby altering the composition of boreal forests., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: To evaluate differences between fasting and nonfasting bile acid levels in asymptomatic and symptomatic pregnant women., Methods: This is a report of two prospective cohort studies describing bile acid levels in the fasting and nonfasting state in pregnancy. The first cohort included asymptomatic women with singleton pregnancies. Women with a diagnosis of cholestasis, symptoms of cholestasis, or intolerance to components of a standardized meal were excluded. Bile acid levels were measured during the second and third trimesters after fasting and again 2 hours after a standardized meal. The second cohort included symptomatic women with singleton pregnancies in whom fasting and nonfasting bile acid levels were measured at the time of symptom evaluation. A cutoff of 10 micromoles/L was used for diagnosis., Results: A total of 27 women were included in the asymptomatic cohort. Median [interquartile range] fasting bile acid levels were significantly lower than nonfasting levels in both the second trimester (4.65 micromoles/L [1.02-29.57] vs 13.62 micromoles/L [2.03-40.26]; P<.001) and third trimester (8.31 micromoles/L [1.14-51.26] vs 17.35 micromoles/L [1.77-62.93]; P<.001). Bile acid levels exceeded 10 micromoles/L in 21% of the fasting samples and in 58% of the nonfasting samples in the third trimester. A total of 26 women were included in the symptomatic cohort. Median [interquartile range] fasting bile acid levels were significantly lower than nonfasting values (11.5 micromoles/L [7-56] vs 13.5 micromoles/L [9-142]; P<.001). Six patients in the symptomatic cohort (23%) had nonfasting bile acid levels greater than 10 micromoles/L that dropped below 10 micromoles/L when fasting., Conclusion: Fasting bile acid levels are significantly lower when compared with nonfasting values in both asymptomatic and symptomatic pregnant women. In asymptomatic women, nonfasting bile acid levels often exceeded 10 micromoles/L whereas fasting values did not. In symptomatic women, fasting bile acid levels resulted in 23% fewer diagnoses of cholestasis when compared with nonfasting values. These findings suggest that fasting evaluation of bile acid levels or a higher threshold for diagnosis of cholestasis should be considered.

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1-treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Pregnant women have been historically excluded from clinical trials for nonobstetric conditions, even during prior epidemics. The objective of this review is to describe the current state of research for pregnant women during the coronavirus disease 2019 (COVID-19) pandemic., Study Design: We conducted a search of international trial registries for trials relating to the novel coronavirus. The eligibility criteria for each trial were reviewed for inclusion/exclusion of pregnant women. Relevant data were extracted and descriptive statistics were calculated for individual and combined data. The total number of trials from each registry were compared, as well as the proportions of pregnancy-related trials within each., Results: Among 621,370 trials in the World Health Organization International Clinical Trials Registry, 927 (0.15%) were COVID-19 related. Of those, the majority (52%) explicitly excluded pregnancy or failed to address pregnancy at all (46%) and only 16 (1.7%) were pregnancy specific. When categorized by region, 688 (74.2%) of COVID-19 trials were in Asia, followed by 128 (13.8%) in Europe, and 66 (7.2%) in North America. Of the COVID-19 trials which included pregnant women, only three were randomized-controlled drug trials., Conclusion: Approximately 1.7% of current COVID-19 research is pregnancy related and the majority of trials either explicitly exclude or fail to address pregnancy. Only three interventional trials worldwide involved pregnant women. The knowledge gap concerning the safety and efficacy of interventions for COVID-19 created by the exclusion of pregnant women may ultimately harm them. While "ethical" concerns about fetal exposure are often cited, it is in fact unethical to habitually exclude pregnant women from research., Key Points: · Pregnancy was excluded from past pandemic research.. · Pregnancy is being excluded from COVID-19 research.. · Exclusion of pregnant women is potentially harmful.., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)