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ABSTRACT Turtles are a small clade of vertebrates despite having existed since the Late Triassic. Turtles have a conservative body plan relative to other amniotes, characterized by the presence of a shell and quadrupedality. This morphology is even retained in strong ecological specialists, such as sea turtles, which are secondarily adapted to marine locomotion by strong allometric scaling in their hands. It is possible that the body plan of turtles is strongly influenced by the presence of the shell, acting as a constraint to achieving greater diversity of body forms. Here, we explore the evolutionary allometric relationships of fore‐ and hindlimb stylopodia (i.e., humerus and femur) with one another as well as their relationship with shell size (carapace length) to assess evidence of constraint. All turtles, including Triassic shelled stem turtles, have near‐isometric relationships that do not vary strongly between clades, and evolve at slow evolutionary rates. This indeed indicates that body proportions of turtles are constrained to a narrow range of possibilities. Minor allometric deviations are seen in highly aquatic sea turtles and softshell turtles, which modified their shells by bone losses. Our allometric regressions allow accurate body size estimations for fossils. Several independent sea turtle lineages converged on maximum sizes of 2.2 m of shell length, which may be a biological maximum for the group.

ABSTRACT Turtles have high shape variation of their mandibles, likely reflecting adaptations to a broad variety of food items and ingestion strategies. Here, we compare functional disparity measured by biomechanical proxies and character disparity measured by discrete morphological characters. Functional and character disparities vary between clades and ecological groups and are thus decoupled. Comparisons with cranial disparity also indicate decoupled patterns within the turtle skull. Exploration of mandibular patterns reveals that several biomechanical configurations or character state combinations can lead to the same feeding type (i.e., convergence) or that high functional disparity can be achieved at a low exhaustion of character state combinations (e.g., cryptodires). Dietary specialists show larger functional disparity than generalists, but the phylogenetically widespread generalist ecology leads to high character disparity signals in the ecotype. Whereas character disparity generally shows high phylogenetic signal, functional disparity patterns correspond to dietary specializations, which may occur convergently across different groups. Despite this, individual functional measurements have overlapping ranges across ecogroups and do not always conform to biomechanical expectations. Jaw opening and closing biomechanical advantages model trade‐offs between force transmission and opening/closing speeds, and turtles show a variety of combinations of values that we try to synthesize into several “jaw types”. Closing mechanical advantage shows that turtles retain high levels of force transmission at the anterior jaw end compared with other groups (e.g., pseudosuchians). This can possibly be explained as an evolutionary adaptation to retain high bite forces at small head sizes.

Abstract Insects play a crucial role in all ecosystems, and are increasingly exposed to higher in temperature extremes under climate change, which can have substantial effects on their abundances. However, the effects of temperature on changes in abundances or population fitness are filtered through differential responses of life‐history components, such as survival, reproduction, and development, to their environment. Such differential responses, or trade‐offs, have been widely studied in birds and mammals, but comparative studies on insects are largely lacking, limiting our understanding of key mechanisms that may buffer or exacerbate climate‐change effects across insect species. Here, we performed a systematic literature review of the ecological studies of lacewings (Neuroptera), predatory insects that play a crucial role in ecosystem pest regulation, to investigate the impact of temperature on life cycle dynamics across species. We found quantitative information, linking stage‐specific survival, development, and reproduction to temperature variation, for 62 species from 39 locations. We then performed a metanalysis calculating sensitives to temperature across life‐history processes for all publications. We found that developmental times consistently decreased with temperature for all species. Survival and reproduction however showed a weaker response to temperature, and temperature sensitivities varied substantially among species. After controlling for the effect of temperature on life‐history processes, the latter covaried consistently across two main axes of variation related to instar and pupae development, suggesting the presence of life‐history trade‐offs. Our work provides new information that can help generalize life‐history responses of insects to temperature, which can then expand comparative demographic and climate‐change research. We also discuss important remaining knowledge gaps, such as a better assessment of adult survival and diapause.

Abstract Flow cytometry‐based immunophenotyping is a mainstay of diagnostics in acute myeloid leukaemia (AML). Aberrant CD56 and T‐cell antigen expression is observed in a fraction subset of AML cases, but the clinical relevance remains incompletely understood. Here, we retrospectively investigated the association of CD56 and T‐cell marker expression with disease‐specific characteristics and outcome of 324 AML patients who received intensive induction therapy at our centre between 2011 and 2019. We found that CD2 expression was associated with abnormal non‐complex karyotype, NPM1 wild‐type status and TP53 mutation. CD2 also correlated with a lower complete remission (CR) rate (47.8% vs. 71.6%, p = 0.03). CyTdT and CD2 were associated with inferior 3‐year event‐free‐survival (EFS) (5.3% vs. 33.5%, p = 0.003 and 17.4% vs. 33.1%, p = 0.02, respectively). CyTdT expression was also correlated with inferior relapse‐free survival (27.3% vs. 48.8%, p = 0.04). In multivariable analyses CD2 positivity was an independent adverse factor for EFS (HR 1.72, p = 0.03). These results indicate a biological relevance of aberrant T‐cell marker expression in AML and provide a rationale to further characterise the molecular origin in T‐lineage‐associated AML.

Abstract Hepatic impairment (HI) moderately (10‐fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A‐mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCRHI). Using physiologically‐based pharmacokinetic modeling and simulation, we predicted relatively well the AUCRHI of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCRHI of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL.

Abstract Conifer forest resilience may be threatened by increasing wildfire activity and compound disturbances in western North America. Fire refugia enhance forest resilience, yet may decline over time due to delayed mortality—a process that remains poorly understood at landscape and regional scales. To address this uncertainty, we used high‐resolution satellite imagery (5‐m pixel) to map and quantify delayed mortality of conifer tree cover between 1 and 5 years postfire, across 30 large wildfires that burned within three montane ecoregions in the western United States. We used statistical models to explore the influence of burn severity, topography, soils, and climate moisture deficit on delayed mortality. We estimate that delayed mortality reduced live conifer tree cover by 5%–25% at the fire perimeter scale and 12%–15% at the ecoregion scale. Remotely sensed burn severity (1‐year postfire) was the strongest predictor of delayed mortality, indicating patch‐level fire effects are a strong proxy for fire injury severity among surviving trees that eventually perish. Delayed mortality rates were further influenced by long‐term average and short‐term postfire climate moisture deficits, illustrating the impact of drought on fire‐injured tree survival. Our work demonstrates that delayed mortality in conifer forests of the western United States can be remotely quantified at a fine grain and landscape scale, is a spatially extensive phenomenon, is driven by fire–climate–environment interactions, and has important ecological implications.

Objective Rheumatic diseases are characterized by different patterns of immune overactivation. This study investigated the correlation of whole blood type 1 interferon (IFN) stimulated gene (ISG), IL18, and CXCL9 expression with clinical disease activity in pediatric rheumatic diseases and assessed the required number of ISGs to be included in a composite type 1 IFN score. Methods Whole blood‐derived RNA and clinical data were collected from 171 mostly pediatric patients with connective tissue diseases (CTDs), systemic autoinflammatory diseases (SAIDs), monogenic interferonopathies (IFNPs) and other inflammatory diseases, and from 38 controls. The expression of six previously established ISGs, IL18, and CXCL9 was assessed by real‐time polymerase chain reaction (471 samples). Individual and composite gene expression was assessed, and correlation and threshold analyses were performed. Results Correlation between ISG expression and clinical disease activity was strongest in CTD, especially in juvenile dermatomyositis (JDM) and IFNP, and modest in patients with SAID. Threshold ISG expression levels for the detection of at least mild clinical disease activity were substantially higher in patients with systemic lupus erythematosus compared with JDM. The correlation of expression levels of limited sets of ISGs and even individual ISGs with clinical disease activity were not inferior to a composite score of six ISGs. Conclusion In a real‐world cohort, individual ISG expression levels robustly reflected clinical disease activity in CTD and IFNP, especially in JDM, which would simplify such analyses in clinical routine and be more cost‐effective. Threshold levels varied across diseases, potentially reflecting different mechanisms of type 1 IFN overactivation.

Abstract Objective Aim of this study was to assess the cost‐effectiveness and cost‐utility of mindfulness‐based cognitive therapy (MBCT) and treatment as usual (TAU) compared to TAU alone in adults with Bipolar disorder (BD). Methods An economic evaluation with a time horizon of 15 months was conducted from a societal perspective. Outcomes were expressed in costs per quality adjusted life years (QALYs) and costs per responder using the inventory of depressive symptomatology clinician rating score. Results People with BD (N = 144) were included in this study. From a societal perspective, the difference of total costs between MBCT + TAU and TAU was €615, with lower costs in the MBCT + TAU group. Only healthcare costs differed significantly between the two groups. A small difference in QALYs in favor of MBCT + TAU was found combined with lower costs (−€836; baseline adjusted) for MBCT + TAU compared to TAU, resulting in a dominant incremental cost‐utility ratio. The probability that the MBCT + TAU was cost‐effective was 65%. All sensitivity analyses attested to the robustness of the base case analyses. Conclusion Concludingly, MBCT + TAU seems to be cost‐effective compared to TAU alone, indicated by a small or neglectable difference in effect, in favor of MBCT + TAU, while resulting in lower costs.

Abstract Immunotherapy has revolutionized the treatment of patients with non‐small cell lung cancer (NSCLC). High expression of tissue PD‐L1 (tPD‐L1) is currently the only approved biomarker for predicting treatment response. However, even tPD‐L1 low (1‐49%) and absent (

Background American Indians face significant barriers to diagnosis and management of cardiovascular disease. We sought to develop a real‐world implementation model for improving access to echocardiography within the Indian Health Service, the American Indian Structural Heart Disease Partnership. Methods and Results The American Indian Structural Heart Disease Partnership was implemented and evaluated via a 4‐step process of characterizing the system where it would be instituted, building point‐of‐care echocardiography capacity, deploying active case finding for structural heart disease, and evaluating the approach from the perspective of the clinician and patient. Data were collected and analyzed using a parallel convergent mixed methods approach. Twelve health care providers successfully completed training in point‐of‐care echocardiography. While there was perceived usefulness of echocardiography, providers found it difficult to integrate screening point‐of‐care echocardiography into their workday given competing demands. By the end of 12 months, 6 providers continued to actively utilize point‐of‐care echocardiography. Patients who participated in the study felt it was an acceptable and effective approach. They also identified access to transportation as a notable challenge to accessing echocardiograms. Over the 12‐month period, a total of 639 patients were screened, of which 36 (5.6%) had a new clinically significant abnormal finding. Conclusions The American Indian Structural Heart Disease Partnership model exhibited several promising strategies to improve access to screening echocardiography for American Indian populations. However, competing priorities for Indian Health Service providers' time limited the amount of integration of screening echocardiography into outpatient practice. Future endeavors should explore community‐based solutions to develop a more sustainable model with greater impact on case detection, disease management, and improved outcomes.

Abstract Erythrodermic mycosis fungoides and Sézary syndrome are chronic, relapsing‐remitting diseases that greatly impacts patients' quality of life (QoL). Mogamulizumab‐kpkc (Mogamulizumab) is a novel therapeutic agent for cutaneous T‐cell lymphomas with a notable impact on progression‐free survival. Qualitative assessment methods allow a broader exploration and greater insight in individual patient experience than quantitative studies. However, there is limited data on the impact of mogamulizumab on health‐related QoL. To investigate the impact of erythrodermic cutaneous T‐cell lymphoma (E‐CTCL) on QoL and the effect of mogamulizumab on the QoL. Semi‐structured interview were conducted with seven patients with E‐CTCL that were receiving mogamulizumab treatment. Five major themes arose: Diagnosis and the diagnostic delay and uncertainty experienced by participants; Physical functioning due to the high symptom burden; Psychological and social functioning considering the significant impact on daily life; Treatment and the effect of mogamulizumab; and Support by family, friends and health professionals. Mogamulizumab therapy resulted in a significant decrease of symptoms. The small sample size should also be taken into account although data saturation was reached. This study gives a broad insight into the large impact of E‐CTCL and the major consequences on the physical functioning as well as on the emotional/psychological and social well‐being. Mogamulizumab appears to have a positive effect on symptoms.

Abstract Quantitative microbiological risk assessment (QMRA) methodology aims to estimate and describe the transmission of pathogenic microorganisms from animals and food to humans. In microbiological literature, the availability of whole genome sequencing (WGS) data is rapidly increasing, and incorporating this data into QMRA has the potential to enhance the reliability of risk estimates. This study provides insight into which are the key pathogen properties for incorporating WGS data to enhance risk estimation, through examination of example risk assessments for important foodborne pathogens: Listeria monocytogenes (Lm), Salmonella, Campylobacter and Shiga toxin‐producing Escherichia coli. By investigating the relationship between phenotypic pathogen properties and genetic traits, a better understanding was gained regarding their impact on risk assessment. Virulence of Lm was identified as a promising property for associating different symptoms observed in humans with specific genotypes. Data from a genome‐wide association study were used to correlate lineages, serotypes, sequence types, clonal complexes and the presence or absence of virulence genes of each strain with patient's symptoms. We also investigated the effect of incorporating WGS data into a QMRA model including relevant genomic traits of Lm, focusing on the dose–response phase of the risk assessment model, as described with the case/exposure ratio. The results highlighted that WGS studies which include phenotypic information must be encouraged, so as to enhance the accuracy of QMRA models. This study also underscores the importance of executing more risk assessments that consider the ongoing advancements in OMICS technologies, thus allowing for a closer investigation of different bacterial subtypes relevant to human health.

Abstract Physiologically based pharmacokinetic models, populated with drug‐metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confidence in the predictive power of such models, they must be validated by comparing the predicted and observed PK of drugs in HI obtained by phenotyping (or probe drug) studies. Therefore, we first predicted the effect of all stages of HI (mild to severe) on the PK of drugs primarily metabolized by cytochrome P450 (CYP) 3A enzymes using the default HI module of Simcyp Version 21, populated with hepatic and intestinal CYP3A abundance data. Then, we validated the predictions using CYP3A probe drug phenotyping studies conducted in HI. Seven CYP3A substrates, metabolized primarily via CYP3A (fraction metabolized, 0.7–0.95), with low to high hepatic availability, were studied. For all stages of HI, the predicted PK parameters of drugs were within twofold of the observed data. This successful validation increases confidence in using the DMET abundance data in HI to predict the changes in the PK of drugs cleared by DMET for which phenotyping studies in HI are not available or cannot be conducted. In addition, using CYP3A drugs as an example, through simulations, we identified the salient PK factors that drive the major changes in exposure (area under the plasma concentration–time profile curve) to drugs in HI. This theoretical framework can be applied to any drug and DMET to quickly determine the likely magnitude of change in drug PK due to HI.

Abstract The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain–machine interfaces and electronic medicine. However, neuroelectrode‐based therapies require invasive neurosurgery and can subject neural tissues to micromotion‐induced mechanical shear, leading to chronic inflammation, the formation of a peri‐electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion‐induced peri‐electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis‐associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo‐type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri‐electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial‐dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri‐electrode void and micromotion‐induced glial scarring at the peri‐electrode region.

Abstract Parenteral prostanoid therapy (PPT) can result in supranormal cardiac index (SCI; >4 L/min/m2) in pediatric pulmonary hypertension (PPH) patients. We evaluated the incidence, hemodynamic factors, and outcomes associated with SCI in PPH. This retrospective cohort study included 22 PPH patients on PPT from 2005 to 2020. Hemodynamic profiles were compared between the baseline and 3–6 month follow‐up catheterization in the SCI and non‐SCI cohorts. Cox regression analysis examined time to composite adverse outcome (CAO; Potts shunt, lung transplant, or death) controlling for initial disease severity. SCI developed in 17 (77%) patients, of whom 11 (65%) developed SCI within 6 months. The SCI cohort was characterized by significant augmentation of cardiac index (CI) and stroke volume (SV) as well as reductions in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). Conversely, the non‐SCI cohort had unchanged SV despite a modest rise in CI as well as persistent vasoconstriction. After median follow‐up of 4.3 years (range 0.2–13 years), non‐SCI patients were at significantly increased risk for the CAO (5/5: three deaths, two Potts shunts) compared with SCI patients (5/17: two deaths, three lung transplants; adjusted hazard ratio 14.0 [95% confidence interval: 2.1–91.3], p

Abstract Double haploid (DH) population development is widely used in many crops, including wheat (Triticum aestivum L.), to rapidly produce fixed germplasm for breeding and genetic studies. The genome shock that takes place during DH induction could induce chromosomal aberrations that can impact genome integrity and subsequently plant fitness and agronomic performance. To evaluate the extent of chromosomal aberrations that exist as a result of the DH process, we studied two wheat DH populations: CDC Stanley×CDC Landmark and KS13H9×SYMonument. We utilized high‐throughput skim sequencing to construct digital karyotypes of these populations to quantify deletions and aneuploidy with high resolution and accuracy, which was confirmed in selected plants by cytological analysis. The two populations studied showed high proportion of abnormal primary DH lines, 55 and 45%, respectively, based on at least one abnormality per progeny. The chromosomal abnormalities are genetically unstable and were observed segregating in the subsequent generations. These observations have important implications for the use of DH lines in genetics and breeding.

Abstract Background Central airway obstruction (CAO) is one of the most challenging, potentially lethal complications in malignant and benign respiratory diseases. Worsening dyspnea is also a relevant cause for reduced quality of life in such patients. Here, we present our data on the application of covered, self‐expanding Y‐carina nitinol stents due to benign and malignant diseases. Methods We retrospectively identified 27 patients who had undergone 31 rigid bronchoscopies with implantation of covered Y‐carina nitinol stents over a period of 10 years in order to evaluate indication, clinical course, and outcome. Results Short‐term survival of successfully stented patients with palliative and curative treatment goal did not differ, allowing for diagnosis independent indication. With respect to overall survival, patients with endoluminal obstruction benefited most compared to patients with fistula and/or external compression. Granulation tissue formation (61.3%) and mucus plugging (80.6%) were the most frequent complications. Material defect (6.5%) and migration (3.2%) were rare complications that could be handled by revisional rigid bronchoscopy and stent exchange in some cases. Conclusions Implantation of self‐expanding covered Y‐carina nitinol stents via rigid bronchoscopy is a feasible and safe treatment option for benign and malignant central airway obstruction. Especially in palliative, malignant airway stenosis, stenting might facilitate additional treatment options and optimize dyspnea and eventually quality of life.

Abstract As one of the key components in model‐informed drug discovery and development, physiologically‐based pharmacokinetic (PBPK) modeling linked with in vitro‐to‐in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug–drug interactions (DDIs) on drug‐metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P‐glycoprotein (Pgp, ABCB1)‐mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis‐Menten constant (Km) to be intrinsic, in vitro‐to‐in vivo scaling factors for maximal Pgp‐mediated efflux rate (Jmax) were optimized based on the clinically observed results without co‐administration of Pgp inhibitors. For Pgp inhibitors, PBPK models utilized the reported in vitro values of Pgp inhibition constants (Ki), 1.0 μM for itraconazole and 2.0 μM for verapamil. Overall, the PBPK modeling sufficiently described Pgp‐mediated DDIs between these substrates and inhibitors with the prediction errors of less than or equal to ±25% in most cases, suggesting a reasonable IVIVE for Pgp kinetics in the clinical DDI results. The modeling results also suggest that Pgp kinetic parameters of both the substrates (Km and Jmax) and the inhibitors (Ki) are sensitive to Pgp‐mediated DDIs, thus being key for successful DDI prediction. It would also be critical to incorporate appropriate unbound inhibitor concentrations at the site of action into PBPK models. The present results support a quantitative prediction of Pgp‐mediated DDIs using in vitro parameters, which will significantly increase the value of in vitro studies to design and run clinical DDI studies safely and effectively.

Abstract Integral projection models (IPMs) are an important tool for studying the dynamics of populations structured by one or more continuous traits (e.g. size, height, body mass). Researchers use IPMs to investigate questions ranging from linking drivers to population dynamics, planning conservation and management strategies, and quantifying selective pressures in natural populations. The popularity of stage‐structured population models has been supported by R scripts and packages (e.g. IPMpack, popbio, popdemo, lefko3) aimed at ecologists, which have introduced a broad repertoire of functionality and outputs. However, pressing ecological, evolutionary and conservation biology topics require developing more complex IPMs, and considerably more expertise to implement them. Here, we introduce ipmr, a flexible R package for building, analysing and interpreting IPMs. The ipmr framework relies on the mathematical notation of the models to express them in code format. Additionally, this package decouples the model parameterization step from the model implementation step. The latter point substantially increases ipmr's flexibility to model complex life cycles and demographic processes. ipmr can handle a wide variety of models, including those that incorporate density dependence, discretely and continuously varying stochastic environments, and multiple continuous and/or discrete traits. ipmr can accommodate models with individuals cross‐classified by age and size. Furthermore, the package provides methods for demographic analyses (e.g. asymptotic and stochastic growth rates) and visualization (e.g. kernel plotting). ipmr is a flexible R package for integral projection models. The package substantially reduces the amount of time required to implement general IPMs. We also provide extensive documentation with six vignettes and help files, accessible from an R session and online.

Abstract Upon diagnosis of pulmonary hypertension in pediatrics, standard practice often involves acute vasoreactivity testing (AVT) in the cardiac catheterization laboratory. However, the importance of repeated AVT testing in a given patient thereafter remains unclear. This study sought to describe serial AVT results in pediatric patients and understand the prognostic significance of longitudinal AVT results in pediatric pulmonary hypertension. A retrospective chart review was performed for pediatric pulmonary hypertension patients diagnosed between 2008 and 2021. Patients were included if they had two or more catheterizations with AVT. The study cohorts were patients who were AVT negative upon initial catheterization then AVT positive at any subsequent catheterization (AVT−/+) compared to those were AVT negative upon initial and all subsequent catheterizations (AVT−/−). A positive AVT was defined by Sitbon criteria. The analyzed outcome was event‐free survival. The relationship between study cohorts and event‐free survival was analyzed by log‐rank Kaplan–Meier survival as well as Cox proportional hazard regression to control for confounders. There were 35 patients who met inclusion criteria in this time period. Patients who were AVT(−/+) had statistically significantly better event‐free survival than AVT(−/−) (p = 0.002). In univariate and multivariate Cox regressions, a subsequent AVT positive result amongst those who were initially AVT negative was a positive prognostic factor, hazard ratio 0.03 (95% confidence interval: 0.02–0.35). For patients with negative AVT upon initial cardiac catheterization, this data supports that continuing AVT should be performed as any subsequent AVT positive result may indicate improved expectations for event‐free survival.

Abstract High‐throughput sequencing approaches, which target a taxonomically discriminant locus, allow for in‐depth insight into microbial communities’ compositions. Although microorganisms are historically investigated by cultivation on artificial culture media, this method presents strong limitations, since only a limited proportion of microorganisms can be grown in vitro. This pitfall appears even more limiting in enological and winemaking processes, during which a wide range of molds, yeasts, and bacteria are observed at the different stages of the fermentation course. Such an understanding of those dynamic communities and how they impact wine quality therefore stands as a major challenge for the future of enology. As of now, although high‐throughput sequencing has already allowed for the investigation of fungal communities, there is no available comparative study focusing on the performance of microbial deoxyribonucleic acid (DNA) extraction in enological matrixes. This study aims to provide a comparison of five selected extraction methods, assayed on both must and fermenting must, as well as on finished wine. These procedures were evaluated according to their extraction yields, the purity of their extracted DNA, and the robustness of downstream molecular analyses, including polymerase chain reaction and high‐throughput sequencing of fungal communities. Altogether, two out of the five assessed microbial DNA extraction methods (DNeasy PowerSoil Pro Kit and E.Z.N.A.® Food DNA Kit) appeared suitable for robust evaluations of the microbial communities in wine samples. Consequently, this study provides robust tools for facilitated upcoming studies to further investigate microbial communities during winemaking using high‐throughput sequencing.

Abstract Understanding how risk factors affect populations across their annual cycle is a major challenge for conserving migratory birds. For example, disease outbreaks may happen on the breeding grounds, the wintering grounds, or during migration and are expected to accelerate under climate change. The ability to identify the geographic origins of impacted individuals, especially outside of breeding areas, might make it possible to predict demographic trends and inform conservation decision‐making. However, such an effort is made more challenging by the degraded state of carcasses and resulting low quality of DNA available. Here, we describe a rapid and low‐cost approach for identifying the origins of birds sampled across their annual cycle that is robust even when DNA quality is poor. We illustrate the approach in the common loon (Gavia immer), an iconic migratory aquatic bird that is under increasing threat on both its breeding and wintering areas. Using 300 samples collected from across the breeding range, we develop a panel of 158 single‐nucleotide polymorphisms (SNP) loci with divergent allele frequencies across six genetic subpopulations. We use this SNP panel to identify the breeding grounds for 142 live nonbreeding individuals and carcasses. For example, genetic assignment of loons sampled during botulism outbreaks in parts of the Great Lakes provides evidence for the significant role the lakes play as migratory stopover areas for loons that breed across wide swaths of Canada, and highlights the vulnerability of a large segment of the breeding population to botulism outbreaks that are occurring in the Great Lakes with increasing frequency. Our results illustrate that the use of SNP panels to identify breeding origins of carcasses collected during the nonbreeding season can improve our understanding of the population‐specific impacts of mortality from disease and anthropogenic stressors, ultimately allowing more effective management.

Abstract Dominant species in intercropping experience less resource competition compared with its monoculture. This reduced competition for resources may allow cultivating the dominant species at an increased density in intercropping to obtain greater yield. However, experimental results are inconclusive when the optimal within row density in the sole crop is not well established. Here, we conducted a two‐year experiment to test the hypothesis that optimal within row plant density of dominant species in intercropping would be higher in the intercrop than in the sole crop. We tested three maize densities (3, 4.5, and 6 plants m−1) in both sole maize and two replacement designed intercrops. The row configurations of two intercrops are two rows maize intercropped with four rows peanut (M2P4) and four rows maize intercropped with four rows peanut (M4P4). Peanut was grown at the same plant density of 12 plants m−1 row in both sole crop and intercrops. The results indicated that increasing maize density from the optimal density in monoculture is not worthy of promotion to improve yield in intercropping, which denied our hypothesis. The land equivalent ratios (LER) in the dry year (2017) were higher than the wet year (2016). Maize yields per unit area of the whole intercropping system were highest with densities of 4.5 and 6 plants m−1 row, with no significant difference between these two densities. Maximum maize yields in sole cropping were obtained with maize densities of 6 plants m−1 row. Intercropping provided higher yields at low and intermediate sole crop maize densities, but not at high sole crop maize density. Average land equivalent ratios at 3, 4.5, and 6 plants m−1 of maize were 1.09, 1.04, and 0.95 in 2016, and 1.07, 1.10, and 1.02 in 2017. Our results suggest that intercropping performs better at conditions with less resources than adequate resources.

Abstract About 40% of non‐small lung cancer (NSCLC) patients have metastatic disease at the time of diagnosis. However, metastatic NSCLC in the biliary duct system is extremely rare. A high proportion of patients with acute liver failure due to advanced NSCLC do not receive any treatment due to organ dysfunction or poor performance status. Here, we report a case of successful treatment with chemoimmunotherapy in a young woman with obstructive jaundice and acute hepatic failure due to multiple intrahepatic bile duct metastases. Key points Significant findings of the study Chemotherapy in NSCLC patients with liver failure is a therapeutic challenge. Acute hepatic failure are often exclusion criteria for therapy of NSCLC. Some reports showed a benefit of ICIs plus chemotherapy for NSCLC with liver metastases. What this study adds Combination of ICIs and chemotherapy is effective and safe in critically ill patients with lung cancer and impaired liver function.

Abstract Objective Adult polyglucosan body disease (APBD) is an adult‐onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods We characterized the effects of knocking out two pro‐glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro‐ and micro‐gliosis in the brains of GYS1‐ and PPP1R3C‐deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

Abstract High‐throughput phenotyping (HTP) has the potential to revolutionize plant breeding by providing scientists with exponentially more data than was available through traditional observations. Even though data collection is rapidly increasing, the optimum use of this data and implementation in the breeding program has not been thoroughly explored. In an effort to apply HTP to the earliest stages of a plant breeding program, we extended field‐based HTP pipelines to evaluate and extract data from spaced single plants. Using a panel of 340 winter wheat (Triticum aestivum L.) lines planted in full plots and grid‐spaced single plants for two growing seasons, we evaluated relationships between single plants and full plot yields. Normalized difference vegetation index (NDVI) was collected multiple times through the growing season using an unoccupied aerial vehicle. NDVI measurements during grain filling stage from both single plants and full plots were typically positively associated with their respective grain yield with correlation ranging from ‐0.22 to 0.74. The relationship between single plant NDVI and full plot yield, however, was variable between seasons ranging from ‐0.40 to 0.06. A genome wide association analysis (GWAS) identified the same marker trait associations in both full plots and single plants, but also displayed variability between growing seasons. Strong genotype by environment interactions could impede selection on quantitative traits, yet these methods could provide an effective tool for plant breeding programs to quickly screen early‐generation germplasm. Efficient use of early‐generation, affordable HTP data could improve overall genetic gain in plant breeding.

Abstract In hard‐winter wheat (Triticum aestivum L.) breeding, the evaluation of end‐use quality is expensive and time‐consuming, being relegated to the final stages of the breeding program after selection for many traits including disease resistance, agronomic performance, and grain yield. In this study, our objectives were to identify genetic variants underlying baking quality traits through genome‐wide association study (GWAS) and develop improved genomic selection (GS) models for the quality traits in hard‐winter wheat. Advanced breeding lines (n = 462) from 2015–2017 were genotyped using genotyping‐by‐sequencing (GBS) and evaluated for baking quality. Significant associations were detected for mixograph mixing time and bake mixing time, most of which were within or in tight linkage to glutenin and gliadin loci and could be suitable for marker‐assisted breeding. Candidate genes for newly associated loci are phosphate‐dependent decarboxylase and lipid transfer protein genes, which are believed to affect nitrogen metabolism and dough development, respectively. The use of GS can both shorten the breeding cycle time and significantly increase the number of lines that could be selected for quality traits, thus we evaluated various GS models for end‐use quality traits. As a baseline, univariate GS models had 0.25–0.55 prediction accuracy in cross‐validation and from 0 to 0.41 in forward prediction. By including secondary traits as additional predictor variables (univariate GS with covariates) or correlated response variables (multivariate GS), the prediction accuracies were increased relative to the univariate model using only genomic information. The improved genomic prediction models have great potential to further accelerate wheat breeding for end‐use quality.