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Abstract The democratisation of next‐generation sequencing has vastly increased the availability of sequencing data from metabarcoding. However, to effectively prepare these metabarcoding data for subsequent analysis, researchers must consistently apply several different bioinformatic tools—including those which denoise reads, cluster sequences and assign taxonomic identities. This often creates a bioinformatics bottleneck in workflows for non‐specialists due to obstacles around: (a) integrating different tools, (b) the inability to easily modify and rerun bioinformatic pipelines involving non‐scripted (‘point‐and‐click’) elements and (c) the multiple outputs that may be required of a single dataset (e.g. amplicon sequence variants [ASVs] and operational taxonomic units [OTUs]), which often results in users running pipelines multiple times. Here, we introduce SimpleMetaPipeline, an open‐source bioinformatics pipeline implemented in R, which addresses these obstacles. SimpleMetaPipeline integrates the most robust and commonly used existing bioinformatic tools in a single reproducible pipeline, with a streamlined choice of parameters, to generate a sequence data table containing alternative clustering and assignment options. SimpleMetaPipeline accepts demultiplexed paired‐end and single reads from multiple sequencing runs. We describe the pipeline and demonstrate how alternative annotations enable the easy implementation of multi‐algorithm agreement tests to strengthen inferences. SimpleMetaPipeline represents a valuable addition to the existing library of pipelines, providing easy and reproducible bioinformatics, including a range of commonly desired clustering and assignment options, such as OTUs and ASVs.

Abstract Objective Despite the availability of pharmacological treatment for seizures, people with epilepsy (PwE) commonly experience impairments in quality of life (QoL). Given the limited access to psychosocial treatments for PwE, digital interventions could bridge treatment gaps and help improve QoL. The objective of this study was to examine the effectiveness of emyna, a fully automated digital intervention based on cognitive behavioral therapy (CBT) techniques, in improving health‐related QoL among PwE who reported impairments in QoL. A previous trial showed that emyna was effective in improving depressive symptoms among PwE with a comorbid depressive disorder, but its effects on QoL among PwE without comorbid depression remain unknown. Methods A pragmatic randomized controlled trial was conducted with N = 438 PwE (mean age = 37.5, 70.3% women, physician‐verified diagnoses) who were assigned to the intervention group (n = 216), which used emyna alongside treatment as usual (TAU), or the control group (n = 222), which received TAU only. QoL and secondary outcomes such as general self‐efficacy, medication adherence, general distress, and epilepsy‐related work and social adjustment were assessed at baseline, 3 months, and 6 months. The primary outcome was QoL assessed with the Quality of Life in Epilepsy [QOLIE‐31] total score at 3 months post‐randomization. Results Findings from the intent‐to‐treat analyses showed that after 3 months, participants in the intervention group experienced significant and clinically relevant improvements in health‐related QoL compared to the control group (baseline‐adjusted group difference = 4.5; 95% CI = [2.0, 6.9], p

Abstract Objective The objective of this study is to investigate whether conductive hearing loss (CHL) can be differentiated from sensorineural hearing loss in children ages 3–18 using a diotic and antiphasic digits‐in‐noise (DIN) tablet‐based test using existing adult cut‐off criteria. Methods A blinded multi‐institutional prospective cohort of 64 children aged 3–18 scheduled for an audiometric soundbooth evaluation with a pediatric audiologist and a same‐day otolaryngologist examination were recruited for the study. Following a conventional audiogram, the subjects underwent diotic (same‐phased stimuli) and antiphasic (out‐of‐phase stimuli) DIN testing on a HearX Samsung Galaxy tablet with over‐the‐ear headphones, for a total of 128 measurements. DIN test results were compared with soundbooth audiometry using known adult “cut off criteria.” Results A logistic regression analysis adjusted for demographics (age, sex) and race was performed to compare CHL determination from DIN testing to CHL determination with soundbooth audiometry. The results showed 50% agreement with a p‐value of .753. The determinations based on combined DIN testing agreed with each other 33% of the time and had a p‐value of .373. Otologic pathology and age were not predictive of outcome. Conclusion This preliminary analysis of DIN testing indicated that DIN and audiometric testing completed in a soundbooth were not significantly predictive of one another in the population of children aged 3–18 when using the adult cut‐off criteria for CHL differentiation. Given these findings, further testing is required in children to determine pediatric specific cut‐off values.

Abstract Background Cell cycle arrest biomarkers (tissue inhibitor of metalloproteinase‐2 [uTIMP‐2] and insulin‐like growth factor binding protein 7 [uIGFBP7]), and neutrophil gelatinase‐associated lipocalin (NGAL) variables are valuable biomarkers for early diagnosis of acute kidney injury (AKI) in people. Objectives To evaluate uTIMP‐2, uIGFBP7, fractional excretion of NGAL (FeNGAL), and urinary to serum NGAL ratio (u/sNGAL) in healthy dogs, dogs with AKI, dogs with chronic kidney disease (CKD), and critically ill (CI) dogs. Animals Forty‐two client‐owned dogs (healthy, n = 10; AKI, n = 11; CKD, n = 11; CI, n = 10). Methods Prospective, observational study. After assessment of routine renal biomarkers, stress (uTIMP‐2, uIGFBP7) and damage (NGAL) biomarkers were measured, using ELISA kits, and normalized to urinary creatinine (uCr). Results Normalized uTIMP‐2 and [uTIMP‐2] × [uIGFBP7]/uCr were significantly higher in the AKI group (median 151.9 [range, 2.2‐534.2] and 62.9 [1.1‐266.8] pg/mL respectively), compared to healthy dogs (0.3 [0.2‐74.7]; P

Abstract Background Acute pulmonary embolism (APE) is a potentially life‐threatening disorder, emphasizing the importance of accurate risk stratification and survival prognosis. The exploration of imaging biomarkers that can reflect patient survival holds the potential to further enhance the stratification of APE patients, enabling personalized treatment and early intervention. Therefore, in this study, we develop computed tomography pulmonary angiography (CTPA) radiomic signatures for the prognosis of 7‐ and 30‐day all‐cause mortality in patients with APE. Methods Diagnostic CTPA images from 829 patients with APE were collected. Two hundred thirty‐four features from each skeletal muscle (SM), intramuscular adipose tissue (IMAT) and both tissues combined (SM + IMAT) were calculated at the level of thoracic vertebra 12. Radiomic signatures were derived using 10 times repeated three‐fold cross‐validation on the training data for SM, IMAT and SM + IMAT for predicting 7‐ and 30‐day mortality independently. The performance of the radiomic signatures was then evaluated on held‐out test data and compared with the simplified pulmonary embolism severity index (sPESI) score, a well‐established biomarker for risk stratification in APE. Predictive accuracy was assessed by the area under the receiver operating characteristic curve (AUC) with a 95% confidence interval (CI), sensitivity and specificity. Results The radiomic signatures based on IMAT and a combination of SM and IMAT (SM + IMAT) achieved moderate performance for the prediction of 30‐day mortality on test data (IMAT: AUC = 0.68, 95% CI [0.57–0.78], sensitivity = 0.57, specificity = 0.73; SM + IMAT: AUC = 0.70, 95% CI [0.60–0.79], sensitivity = 0.74, specificity = 0.54). Radiomic signatures developed for predicting 7‐day all‐cause mortality showed overall low performance. The clinical signature, that is, sPESI, achieved slightly better performance in terms of AUC on test data compared with the radiomic signatures for the prediction of both 7‐ and 30‐day mortality on the test data (7 days: AUC = 0.73, 95% CI [0.67–0.79], sensitivity = 0.92, specificity = 0.16; 30 days: AUC = 0.74, 95% CI [0.66–0.82], sensitivity = 0.97, specificity = 0.16). Conclusions We developed and tested radiomic signatures for predicting 7‐ and 30‐day all‐cause mortality in APE using a multicentric retrospective dataset. The present multicentre work shows that radiomics parameters extracted from SM and IMAT can predict 30‐day all‐cause mortality in patients with APE.

Abstract Background Neurogenic dysphagia is a frequent complication of stroke and is associated with aspiration pneumonia and poor outcomes. Although ischaemic lesion location and size are major determinants of the presence and severity of post‐stroke dysphagia, little is known about the contribution of other acute stroke‐unrelated factors. We aimed to analyse the impact of swallowing and non‐swallowing muscles measurements on swallowing function after large vessel occlusion stroke. Methods This retrospective study was based on a prospective registry of consecutive ischaemic stroke patients. Patients who underwent mechanical thrombectomy between July 2021 and June 2022 and received a flexible endoscopic evaluation of swallowing (FEES) within 5 days after admission were included. Demographic, anthropometric, clinical, and imaging data were collected from the registry. The cross‐sectional areas (CSA) of selected swallowing muscles (as a surrogate marker for swallowing muscle mass) and of cervical non‐swallowing muscles were measured in computed tomography. Skeletal muscle index (SMI) was calculated and used as a surrogate marker for whole body muscle mass. FEES parameters, namely, Functional Oral Intake Scale (FOIS, as a surrogate marker for dysphagia presence and severity), penetration aspiration scale, and the presence of moderate‐to‐severe pharyngeal residues were collected from the clinical records. Univariate and multivariate ordinal and logistic regression analyses were performed to analyse if total CSA of swallowing muscles and SMI were associated with FEES parameters. Results The final study population consisted of 137 patients, 59 were female (43.1%), median age was 74 years (interquartile range 62–83), median baseline National Institutes of Health Stroke Scale score was 12 (interquartile range 7–16), 16 patients had a vertebrobasilar occlusion (11.7%), and successful recanalization was achieved in 127 patients (92.7%). Both total CSA of swallowing muscles and SMI were significantly correlated with age (rho = −0.391, P

Abstract Aims Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF

Abstract Warm Airmass Intrusions (WAIs) from the mid‐latitudes significantly impact the Arctic water budget. Here, we combine water vapor isotope measurements from the MOSAiC expedition, with a Lagrangian‐based process attribution diagnostic to track moisture transformation in the central Arctic Ocean during two WAIs, under contrasting sea‐ice concentrations (SIC). During winter with high SIC, two moisture supplies are identified. The first is Arctic moisture, locally‐sourced over the sea ice, with isotopic composition influenced by kinetic fractionation during ice‐cloud formation and vapor deposition. This moisture is rapidly overprinted by low‐latitude moisture advected poleward during WAI. In summer under low SIC, moisture is supplied through evaporation from land and ocean, with moisture removal via liquid‐cloud and dew formation. The isotopic composition reflects the influence of higher relative humidity at the evaporation sites. Given the projected increase of frequency and duration of WAIs, our study contributes to assessing process changes in the Arctic water cycle.

Background In the management of patients resuscitated from out‐of‐hospital cardiac arrest, a primary goal is to restore sufficient oxygen delivery (DO2) to meet demands in oxygen consumption (VO2). Methods and Results This post hoc analysis of the BOX (Blood Pressure and Oxygen Targets) study included adult patients who were comatose and experienced out‐of‐hospital cardiac arrest from a presumed cardiac cause, who were randomized to a mean arterial blood pressure (MAP) target of 63 mm Hg (MAP63) or 77 mm Hg (MAP77) and a Restrictive PaO2 target of 9 to 10 kPa versus a Liberal target of 13 to 14 kPa in a 2×2 factorial design. A pulmonary artery catheter was inserted following randomization. DO2 and VO2 were calculated as: DO2=cardiac output × arterial oxygen content, and VO2= cardiac output × arteriovenous oxygen difference. Of 789 patients, 730 (92.5%) were included in this substudy. A total of 362 patients were randomized to MAP77, and 368 to MAP63, 368 to a liberal Pao2 target, and 362 to a restrictive target. At all prespecified time points, DO2 in MAP77 was higher compared with MAP63, with a cumulative treatment effect of 203 L (95% CI, 132–274) O2 after 36 hours. VO2 was higher in MAP77 after 36 hours, with a cumulative treatment effect of 21.9 L (95% CI, 5.8–38) O2, compared with the MAP63 group. Conclusions Targeting a MAP of 77 mm Hg resulted in an overall increase in DO2 and a smaller increase in VO2 compared with a MAP target of 63 mm Hg. A higher Pao2 target did not result in any difference in DO2 or VO2.

Abstract Ezetimibe undergoes glucuronidation that results in the active metabolite ezetimibe phenoxy‐glucuronide (ezetimibe‐glucuronide). This phase‐II metabolite was shown to interact with the clinically relevant hepatic transporter organic anion transporting polypeptide (OATP) 1B1. In recent years, coproporphyrin I (CPI) was established as a Tier 1 biomarker for OATP1B‐mediated interactions among other endogenous substrates like CPIII. To evaluate whether levels of the biomarker are affected by ezetimibe treatment, we assessed the impact of ezetimibe and ezetimibe‐glucuronide on OATP1B1‐mediated transport of CPs in vitro. Then, we quantified CP levels in serum samples of healthy volunteers treated with a single oral dose of ezetimibe (20 mg) alone or in combination with rifampin (600 mg). Results from our in vitro experiments showed a significant reduction in cellular CPI accumulation in the presence of ezetimibe‐glucuronide with an IC50 of 1.97 μM [95% CI: 1.04 to 3.96], while CPIII accumulation was impacted by 10 μM and above. In the in vivo study, we observed peak CP concentrations 1.33 h after dosing, which is closest to the tmax of the ezetimibe metabolite. Co‐administration of ezetimibe with rifampin resulted in even higher serum CP levels. The AUC0–24h of CPI and CPIII increased two‐ and threefold, respectively, after concomitant dosing compared to ezetimibe alone. Moreover, we quantified CP levels in cumulative urine from both study phases where the renally excreted amount (Ae) of CPI and CPIII increased after ezetimibe and rifampin co‐administration compared to ezetimibe alone. In conclusion, our findings indicate that rifampin co‐administration results in additional inhibition of OATP1B1 in vivo.

Abstract Understanding the mechanisms underlying amyloid‐β (Aβ) aggregation is pivotal in the context of Alzheimer's disease. This study aims to elucidate the secondary nucleation process of Aβ42 peptides by combining experimental and computational methods. Using a newly developed nanopipette‐based amyloid seeding and translocation assay, confocal fluorescence spectroscopy, and molecular dynamics simulations, the influence of the seed properties on Aβ aggregation is investigated. Both fragmented and unfragmented seeds played distinct roles in the formation of oligomers, with fragmented seeds facilitating the formation of larger aggregates early in the incubation phase. The results show that secondary nucleation leads to the formation of oligomers of various sizes and structures as well as larger fibrils structured in β‐sheets. From these findings a mechanism of secondary nucleation involving two types of aggregate populations, one released and one growing on the mother fiber is proposed.

Abstract Despite a substantial impact on various economic and cell technology factors, the influence of electrolyte quantities is rarely addressed in research. This study examines the impact of varying electrolyte quantities on cell performance and aging processes using three different electrolytes: LP57 (1 M LiPF6 in ethylene carbonate:ethyl methyl carbonate (EC:EMC 3:7 w/w), LP572 (LP57+2 wt.% vinylene carbonate (VC)) and LP57 + absVC (18.351 mg VC). Comprehensive analytical post mortem investigations revealed that continuous excessive electrolyte decomposition determines the performance of cells using LP57, leading to enhanced irreversible lithium‐ion loss and interphase thickening with increasing electrolyte volume. Impedance rise due to the growth of the interphase was also identified as the cause of degrading cell performance with rising amounts of LP572, attributed to an increasingly pronounced consumption of VC rather than electrolyte aging effects. By varying the electrolyte quantity while maintaining a constant amount VC within the cell system, the differences in cell performance were minimized, and observed deteriorating effects were suppressed. This study demonstrates the sensitive interdependence of electrolyte volume and additive concentration, practically affecting aging behavior. Comprehensively understanding the characteristics of each individual electrolyte component and tailoring the electrolytes to cell‐specific cell properties proves to be crucial to optimize cell performance.

Background Whether cardiovascular dysfunction is associated with preeclampsia in women without fetal growth restriction (FGR) is unclear. Our objective was to investigate associations between third‐trimester cardiac output (CO) and systemic vascular resistance and risk of hypertensive disorders of pregnancy in women with and without FGR. Methods and Results A case–cohort study in 906 pregnant women in Denmark with repeated third‐trimester cardiac function assessments was performed using the Ultrasound Cardiac Output Monitor 1A. Using Cox regression, we compared rates of hypertensive disorders of pregnancy in women with low, normal, and high CO and normal and high systemic vascular resistance, by FGR status and gestational age, and evaluated associations between a third‐trimester drop in CO or increase in systemic vascular resistance and preeclampsia risk in women without FGR. The analysis included 249 women with preeclampsia (42 with FGR) and 119 women with gestational hypertension. Low CO was strongly associated with preeclampsia at 75th percentile and preeclampsia in women without FGR (odds ratio, 1.91 [95% CI, 0.84–4.36]). High systemic vascular resistance was strongly associated with increased rates of all forms of hypertensive disorders of pregnancy. Conclusions Low CO is associated with preeclampsia risk in women with and without FGR, particularly before 37 weeks. Repeated measurements of third‐trimester cardiovascular function might identify women without FGR for monitoring for preeclampsia, but this result needs to be confirmed in other studies.

Abstract Aims There is a growing body of literature on long‐term outcomes post‐transcatheter aortic valve replacement (TAVR), but to our knowledge, few research have focused on patients with advanced cardiac dysfunction. This challenging category of patients was excluded from the Partner 3 clinical trial. There are no data to guide the choice of valve type in patients with severely depressed ejection fraction. This study evaluates the safety, efficacy, and outcomes of TAVR in patients with severe aortic stenosis and left ventricular ejection fraction (LVEF) ≤ 35%. It compares post‐TAVR survival outcomes with self‐expanding (SEV) versus balloon‐expandable (BEV) valves in the context of cardiac dysfunction. Methods and results A retrospective cohort was conducted on 977 patients who underwent TAVR at Toulouse University Hospital between January 2016 and December 2020. The study population included two groups: LVEF ≤ 35% (N = 157) and LVEF ≥ 50% (N = 820). The group of LVEF ≤ 35% was divided into two subgroups according to the type of implanted device: self‐expanding (N = 66) versus balloon‐expandable (N = 91). The living status of each of study's participants was observed in December 2022. Patients with low ejection fraction were younger (82 vs. 84.6 years) and commonly males (71.3% vs. 45.6%). Procedural success was almost 98% in both study groups (97.5% vs. 97.9%). The prevalence of all in‐hospital post‐TAVR complications [acute kidney injury (3.8% vs. 2.2%), major bleeding events (2.5% vs. 3.2%), stroke (1.3% vs. 1.6%), pacemaker implantation (10.2% vs. 10.7%), major vascular complication (4.5% vs. 4.5%), new onset atrial fibrillation (3.2% vs. 3.4%), and in‐hospital death (3.2% vs. 2.8%)] were similar between groups (LVEF ≤ 35% vs. LVEF ≥ 50%). No difference in long‐term survival has been revealed over 3.4 years (P = 0.268). In patients with LVEF ≤ 35%, except for post‐TAVR mean aortic gradient (7.8 ± 4.2 vs. 10.2 ± 3.6), baseline and procedural characteristics were comparable between SEV versus BEV subgroups. An early improvement in LVEF (from 29.2 ± 5.5 to 37.4 ± 10.8) was observed. In patients with LVEF ≤ 35%, the all‐cause mortality rate was significantly higher in BEV than that in SEV subgroups, respectively (40.7% vs. 22.7%, P = 0.018). Kaplan–Meier curve showed better survival outcomes after SEV implantation (P = 0.032). A Cox regression identified BEV as independent predictor of mortality [HR = 3.276, 95% CI (1.520–7.060), P = 0.002]. Conclusions In the setting of low LVEF, TAVR remains a safe and effective procedure not associated with an increased risk of complications and mortality. SEV implantation may likely result in superior survival outcomes in patients with advanced cardiac dysfunction.

Abstract Aims Peripartum cardiomyopathy (PPCM) is characterized by left ventricular (LV) dysfunction developing towards the end of pregnancy or in the first months postpartum. Although about 60% of women with PPCM (the majority of which are prescribed evidence based heart failure [HF] medications) show LV recovery within 6 to 12 months, others remain with persistently impaired LV function. Poor adherence to medical therapy represents a major cause of avoidable hospitalizations, disability, and death in other cardiovascular conditions. In this study, we aimed to determine drug adherence to HF therapy among women with PPCM and to identify possible associations between drug adherence and LV recovery, functional status and psychological well‐being. Methods and results In this single‐centre, prospective, observational study, we included 36 consecutive women with PPCM. Adherence to HF treatment was assessed by (i) verifying the collection of pharmacy refills and (ii) using liquid chromatography high‐resolution mass spectrometry (LC‐HRMS). Participants were thereby classified as ‘adherent’ (i.e. all prescribed HF drugs were detectable by LC‐HRMS), ‘partially adherent’ (i.e. at least one prescribed drug detectable) or ‘non‐adherent’ (i.e. none of the prescribed drugs detectable). Health state index scores were assessed by EQ‐5D‐5L and HADS‐A/D (for anxiety/depression). Patients' median age was 32.4 years (IQR 27.6–36.1). At the adherence visit (which occurred at a median of 16 months [IQR 5–45] after PPCM diagnosis), prescription included beta‐blockers (77.8%), angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers (75%), mineralocorticoid receptor antagonists (47.2%) and loop diuretics (95.2%). Less than two thirds of patients (63.9%) collected all their pharmacy refills in the 6 months prior to adherence visit. According to LC‐HRMS, 23.5% participants were classified as adherent, 53.0% as partially adherent, and 23.5% as non‐adherent. Adherence was associated with significantly lower LVEDD at follow‐up (47 mm [IQR 46–52), vs. 56 mm [IQR 49–64] with partial adherence, and 62 mm [IQR 55–64] with non‐adherence, P = 0.022), and higher LVEF at follow‐up (60% [IQR 41–65]), vs. partially adherence (46% [IQR 34–50]) and non‐adherence (41.0% [IQR 29–47], P = 014). Adherent patients had a lower overall EQ‐ 5D score (5.5 [IQR 5–7.5], vs. 6 [IQR 5–7] in partially adherent, and 10 [IQR 8–15] in non‐adherent patients, P = 0.032) suggestive of a better self‐rated health status. Conclusions Adherence to HF therapy was associated with favourable LV reverse remodelling in PPCM and better self‐rated health status. Our study highlights the importance of drug adherence for functional recovery. Drug adherence should be an important component of patient communication and specific interventions in PPCM.

Abstract Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration–effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

Abstract Background Duchenne muscular dystrophy (DMD) is an X‐linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early‐stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age‐dependent DCM. Methods Here, we used hiPSC‐CMs from DMD patients selected by Speckle‐tracking echocardiography and canine DMD cardiac biopsies to assess key early‐stage Duchenne DCM features. Results Dystrophin deficiency was associated with RyR2 remodelling and SR Ca2+ leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P

Abstract Nature's contributions to people (NCP) are essential for the production and trade of agricultural, forestry and fishery commodities. Often, there is a spatial disconnect between consumers and the natural systems where the commodities are produced. Traded agricultural products are therefore dependent on nature and NCP in their region of origin. The dependencies of agricultural products on NCP are, however, insufficiently recognised by consumers and are rarely considered in global environmental governance and trade policies along value chains. Here, we synthesise studies highlighting dependencies of agricultural products on NCP in their origin locations to identify opportunities and challenges in quantifying their contribution in sustaining trade flows. We suggest three methodological steps for quantifying NCP dependencies in international agricultural trade: spatial mapping of NCP supply and demand, linking NCP to agricultural trade flows, and tracing trade flows. Each methodological step requires further development and harmonisation to enable a complete accounting of how international agricultural trade depends on NCP. Given the lack of knowledge and data on how NCP support agricultural trade, social and environmental trade‐offs of natural resource management are currently hard to quantify. Quantifying the role of NCP dependencies of traded agricultural products can support their sustainable management, contribute to supply chain accountability and serve as input to sustainable natural resource governance and foster responsibility and equity in supply chains. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Filamentous fungi with their diverse inventory of carbohydrate‐active enzymes promise a holistic usage of lignocellulosic residues. A major challenge for application is the inherent repression of enzyme production by carbon catabolite repression (CCR). In the presence of preferred carbon sources, the transcription factor CreA/CRE‐1 binds to specific but conserved motifs in promoters of genes involved in sugar metabolism, but the status of CCR is notoriously difficult to quantify. To allow for a real‐time evaluation of CreA/CRE‐1‐mediated CCR at the transcriptional level, we developed a luciferase‐based construct, representing a dynamic, highly responsive reporter system that is inhibited by monosaccharides in a quantitative fashion. Using this tool, CreA/CRE‐1‐dependent CCR triggered by several monosaccharides could be measured in Neurospora crassa, Aspergillus niger and Aspergillus nidulans over the course of hours, demonstrating distinct and dynamic regulatory processes. Furthermore, we used the reporter to visualize the direct impacts of multiple CreA truncations on CCR induction. Our reporter thus offers a widely applicable quantitative approach to evaluate CreA/CRE‐1‐mediated CCR across diverse fungal species and will help to elucidate the multifaceted effects of CCR on fungal physiology for both basic research and industrial strain engineering endeavours.

Abstract Meristic traits are often treated as distinct phenotypes that can be used to differentiate and delineate recently diverged species. For instance, the number of lateral line scales and vertebrae, two traits that vary substantially among Neotropical Heroine cichlid species, have been previously suggested to co‐evolve. These meristic traits could co‐evolve due to shared adaptive, developmental, or genetic factors. If they were found to be genetically or developmentally non‐independent, this might require a more general re‐evaluation of their role in evolutionary or taxonomic studies. We expanded a previous analysis of correlated evolution of meristic traits (lateral line scales and vertebrae counts) in these fishes to include a range of phylogenetic reconstructions as well as the analyses of 13 Nicaraguan Midas cichlid species (Amphilophus spp.). Additionally, we performed qualitative traits locus (QTL) mapping in a F2 laboratory‐reared hybrid population from two ecologically divergent Midas cichlid fish species to discover and evaluate whether genomic co‐segregation might explain the observed patterns of meristic co‐evolution. Meristic values for these traits were found to morphologically differentiate some species of the Midas cichlid adaptive radiation. Our QTL analysis pinpointed several genomic regions associated with divergence in these traits and highlighted the potential for genomic co‐segregation of the lateral line and vertebrae numbers on two chromosomes. Further, our phylogenetic comparative analyses consistently recovered a significant positive evolutionary correlation between the counts of lateral line scale and vertebrae numbers in Neotropical cichlids. Hence, the findings of genomic co‐segregation could partially explain the co‐evolution of these two meristic traits in these species. Continuing to unravel the genetic architecture governing meristic divergence helps to better understand both trait correlations and the utility of meristic traits in taxonomic diagnoses and how traits in phenotypes might be expected to co‐evolve.

ABSTRACT Background Texture analysis derived from computed tomography (CT) may provide clinically relevant imaging biomarkers associated with tumor histopathology. Perihilar cholangiocarcinoma is a malignant disease with an overall poor prognosis. Aims The present study sought to elucidate possible associations between texture features derived from CT images with grading, tumor markers, and survival in extrahepatic, perihilar cholangiocarcinomas tumors. Methods This retrospective study included 22 patients (10 females, 45%) with a mean age of 71.8 ± 8.7 years. Texture analysis was performed using the free available Mazda software. All tumors were histopathologically confirmed. Survival and clinical parameters were used as primary study outcomes. Results In discrimination analysis, “S(1,1)SumVarnc” was statistically significantly different between patients with long‐term survival and nonlong‐term survival (mean 275.8 ± 32.6 vs. 239.7 ± 26.0, p = 0.01). The first‐order parameter “skewness” was associated with the tumor marker “carcinoembryonic antigen” (CEA) (r = −0.7, p = 0.01). A statistically significant correlation of the texture parameter “S(5,0)SumVarnc” with tumor grading was identified (r = −0.6, p

Abstract Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long‐term side effects induced by chemo‐ and radiotherapy. cHL tumors are characterized by the low fraction (0.1%–10%) of malignant Hodgkin and Reed–Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD‐1/PD‐L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single‐cell RNA sequencing (scRNA‐seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides TNFRSF8 (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as NRXN3 and LRP8, which can potentially be used as alternative targets for antibody–drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin‐1/CD69 and HLA‐II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor‐immune cell interactions.

Abstract Animals occupying higher trophic levels can have disproportionately large influence on ecosystem structure and functioning, owning to intricate behavioral responses to their environment, but the effects of behavioral adaptations on aquatic ecosystem dynamics are underrepresented, especially in model studies. Here, we explore how adaptive behavior of fish can affect the dynamics of aquatics ecosystems. We frame fish behavior in the context of the central trade‐off between feeding and predation, calculating the optimal level of feeding determined by ambient food availability and predation risk. To explore whole‐ecosystem consequences of fish behavior, we embed our behavioral model within the Water Ecosystems Tool (WET), a contemporary end‐to‐end aquatic ecosystem model. The principle of optimality provides a robust and mechanistic framework for representing animal behavior that is relevant for complex models, and can provide a stabilizing effect on model dynamics. The model predicts an emergent functional response similar to Holling type III, but with richer dynamics and a more rigorous theoretical foundation. We show how adaptive fish behavior works to stabilize food web dynamics compared to a control model with no optimal behavior, and how changing the strength of the underlying trade‐off has profound effects on trophic control and food web structure. Furthermore, we demonstrate how including fish behavior allows for an overall more realistic response of the model system to environmental perturbation in the form of nutrient enhancement. We discuss the structuring effects of behavioral adaptations in real ecosystems, and how approaches like this one may benefit aquatic ecological modeling. Our study further highlights how a mechanistic approach based on concepts from theoretical ecology can be successfully implemented in complex operational models resulting in improved dynamics and descriptive power.

Abstract In movement analysis, correlated random walk (CRW) models often use so‐called turning angles, which are measured relative to the previous movement direction. To segregate between different movement modes, hidden Markov models (HMMs) describe movements as piecewise stationary CRWs in which the distributions of turning angles and step sizes depend on the underlying state. This typically allows for the segregation of movement modes that show different movement speeds. We show that in some cases, it may be interesting to investigate absolute angles, that is, biased random walks (BRWs) instead of turning angles. In particular, while discrimination between states in the turning angle setting can only rely on movement speed, models with absolute angles can be used to discriminate between sections of different movement directions. A preprocessing algorithm is provided that enables the analysis of absolute angles in the existing R package moveHMM. In a data set of movements of cell organelles, models using not the turning angle but the absolute angle could capture interesting additional properties. Goodness‐of‐fit was increased for HMMs with absolute angles, and HMMs with absolute angles tended to choose a higher number of states, suggesting the existence and relevance of prominent directional changes in the present data set. These results suggest that models with absolute angles can provide important information in the analysis of movement patterns if the existence and frequency of directional changes is of biological importance.

Abstract Two outstanding questions for the future of the Greenland Ice Sheet are (a) how enhanced meltwater draining beneath the ice will impact the behavior of large tidewater glaciers, and (b) to what extent tidewater glacier velocity is driven by changes at the terminus versus changes in sliding velocity due to meltwater. We present a two‐way coupled framework to simulate the nonlinear feedbacks of evolving subglacial hydrology and ice dynamics using the Subglacial Hydrology And Kinetic, Transient Interactions (SHAKTI) model within the Ice‐sheet and Sea‐level System Model (ISSM). Through coupled simulations of Helheim Glacier, we find that terminus effects dominate the seasonal velocity pattern up to 15 km from the terminus, while hydrology drives the velocity response upstream. With increased melt, the hydrology influence yields seasonal acceleration of several hundred meters per year in the interior, suggesting that hydrology will play an important role in future mass balance of tidewater glaciers.

Abstract Introduction There is a dearth of research on cognitive aging and dementia in Asian Americans, particularly in Vietnamese Americans, the fourth largest Asian subgroup in the United States. Methods The Vietnamese Insights into Cognitive Aging Program (VIP) investigates early life adversity and war‐related trauma and their associations with cognitive health in a community‐based sample of older Vietnamese Americans in Northern California (i.e., Sacramento and Santa Clara counties). Baseline measurements include a comprehensive neuropsychological battery, including measures of global cognition along with executive function, semantic memory, and episodic memory. Data also include measures of functioning, early life adversity and trauma exposure, and psychosocial and traditional cardiovascular disease risk factors. Cognitive assessments will be repeated twice over the course of the data collection period, approximately 12‐ and 24‐ months post‐baseline. Blood samples collected during Wave 2 will be assayed for biochemical risk factors. Results Baseline assessments were conducted from January 2022 to November 2023, with N = 548 Vietnamese Americans; mean age ± SD was 73 ± 5.31 years and 55% of participants were women. There were significant differences in social factors by site, with Santa Clara participants having higher education (some college or higher: Sacramento, ≈25%; Santa Clara: ≈48%) and marginally higher incomes compared to Sacramento participants. A higher percentage of Santa Clara participants reported speaking English well or very well (24%) compared to Sacramento participants (13%), although the majority of the entire sample (81%) reported speaking some to no English (response options: not at all; some/a little bit; well/very well). Discussion This longitudinal study providea a unique opportunity to more fully delineate psychosocial factors that contribute to dementia disparities in diverse and under‐engaged populations. Future work will examine cognition, the prevalence of mild cognitive impairment and dementia, and other health outcomes, while controlling for site differences in all analyses. Highlights Vietnamese Insights into Cognitive Aging Program (VIP) is a new study. VIP has detailed early life and health data on 548 older Vietnamese Americans. History of war and trauma may contribute to Alzheimer's disease and related dementias (ADRD)–related burden. VIP may provide insight into ADRD burden in other understudied groups.

Abstract The oilseed palm genus Acrocomia is suitable for sustainable oil production in South America. The high phenotypic diversity of wild populations poses a challenge for the delimitation of the genus. Comparing the inflorescence architecture, a first‐order panicle, and staminate and pistillate flower traits could be a valuable tool in resolving the taxonomic disarray. Thus, this study aims to characterize the differences in the inflorescence architecture and floral structures of three common and economically significant Acrocomia species: A. aculeata, A. totai, and A. intumescens. Biometric traits of the inflorescence architecture and floral structures of various Acrocomia accessions in an ex situ germplasm collection in Brazil were assessed. The unweighted pair group method with arithmetic mean (UPGMA) cluster analysis based on the Gower distance was used to measure dissimilarities between the individual plants of the accessions. To our best knowledge, this study provides the first evidence of the presence of second‐order rachillae in the genus Acrocomia. Evaluated traits showed a high level of variation within and between accessions, emphasizing the phenotypic diversity of the genus. The accessions of A. totai were distinguishable from those of the other two species by their inflorescence architecture and flower traits. The dissimilarities between A. aculeata and A. intumescens were not sufficient to differentiate both. In conclusion, the quantitative assessment of inflorescence and floral traits is a valuable tool for taxonomic resolution of the genus.

Abstract Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug–drug interactions (DDIs). ACT‐1004‐1239 is a potent and selective, first‐in‐class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT‐1004‐1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single‐dose ACT‐1004‐1239 in healthy male subjects. In the open‐label, fixed‐sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT‐1004‐1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT‐1004‐1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0−∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well‐tolerated with an identical incidence in subjects reporting treatment‐emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT‐1004‐1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2‐ to

Abstract Twenty percent of children with T‐cell lymphoblastic lymphoma (T‐LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low‐risk subgroup in pediatric T‐LBL, yet these high‐risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high‐risk T‐LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T‐LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high‐risk biological subgroup of children with T‐LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T‐LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C‐C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T‐cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy‐related acute myeloid leukemia during maintenance therapy. These data indicate that T‐LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.

Abstract Duplicated genes provide the opportunity for evolutionary novelty and adaptive divergence. In many cases, having more gene copies increases gene expression, which might facilitate adaptation to stressful or novel environments. Conversely, overexpression or misexpression of duplicated genes can be detrimental and subject to negative selection. In this scenario, newly duplicate genes may evade purifying selection if they are epigenetically silenced, at least temporarily, leading them to persist in populations as copy number variations (CNVs). In animals and plants, younger gene duplicates tend to have higher levels of DNA methylation and lower levels of gene expression, suggesting epigenetic regulation could promote the retention of gene duplications via expression repression or silencing. Here, we test the hypothesis that DNA methylation variation coincides with young duplicate genes that are segregating as CNVs in six populations of the three‐spined stickleback that span a salinity gradient from 4 to 30 PSU. Using reduced‐representation bisulfite sequencing, we found DNA methylation and CNV differentiation outliers rarely overlapped. Whereas lineage‐specific genes and young duplicates were found to be highly methylated, just two gene CNVs showed a significant association between promoter methylation level and copy number, suggesting that DNA methylation might not interact with CNVs in our dataset. If most new duplications are regulated for dosage by epigenetic mechanisms, our results do not support a strong contribution from DNA methylation soon after duplication. Instead, our results are consistent with a preference to duplicate genes that are already highly methylated.

Abstract The number of multidrug‐resistant strains of bacteria is increasing rapidly, while the number of new antibiotic discoveries has stagnated. This trend has caused a surge in interest in bacteriophages as anti‐bacterial therapeutics, in part because there is near limitless diversity of phages to harness. While this diversity provides an opportunity, it also creates the dilemma of having to decide which criteria to use to select phages. Here we test whether a phage's ability to coevolve with its host (evolvability) should be considered and how this property compares to two previously proposed criteria: fast reproduction and thermostability. To do this, we compared the suppressiveness of three phages that vary by a single amino acid yet differ in these traits such that each strain maximized two of three characteristics. Our studies revealed that both evolvability and reproductive rate are independently important. The phage most able to suppress bacterial populations was the strain with high evolvability and reproductive rate, yet this phage was unstable. Phages varied due to differences in the types of resistance evolved against them and their ability to counteract resistance. When conditions were shifted to exaggerate the importance of thermostability, one of the stable phages was most suppressive in the short‐term, but not over the long‐term. Our results demonstrate the utility of biological therapeutics' capacities to evolve and adjust in action to resolve complications like resistance evolution. Furthermore, evolvability is a property that can be engineered into phage therapeutics to enhance their effectiveness.

Abstract Background Mammary adenocarcinomas are one of the most common tumour diseases in bitches. The relationship between oxidative stress and the degree of malignancy of the tumour has not been sufficiently researched in veterinary medicine. Objectives The main objective was to investigate the potential role of MDA as a practice‐relevant biomarker for the assessment of systemic oxidative stress and to determine whether this parameter can indicate the malignancy grade of a mammary adenocarcinoma. Methods In the present pilot study, MDA plasma concentrations were analysed in 55 bitches with (n = 28) and without (n027) malignant adenocarcinomas of the mammary gland using two different measurement methods and the relationship to tumour size was investigated. Results The mean MDA concentration measured by enzyme‐linked immunosorbent assay (ELISA) was 289 ng/mL (range 365–634 ng/mL) in dogs with grade 1 adenocarcinoma (n = 13), 288.5 ng/mL (range 85–752 ng/mL) in dogs with grade 2 adenocarcinoma (n = 10), 332 ng/mL (range 239–947 ng/mL) in dogs with grade 3 (n = 5) adenocarcinoma and 293 ng/mL (range 175–549 ng/mL) in dogs without a mammary tumour (n = 27). When MDA was measured by HPLC, the average MDA concentration in the study group (n = 11) was 0.24 µmol/L (range 0.16–0.37) and that of the control group (n = 15) was 0.27 µmol/L (range 0.16–1.62). Thus, there were no significant differences between the study group with malignant adenocarcinomas and the control group in both examination methods (p > 0.05). Furthermore, there was no correlation between the MDA concentrations and the approximate volume of the mammary tumour. Conclusion The results highlight the challenges of providing a prognosis for the malignancy of a mammary adenocarcinoma based on MDA concentrations in plasma using ELISA or HPLC. As a result, histopathological examination remains the gold standard for diagnosing and differentiating adenocarcinomas of the mammary gland.

Background Patient outcome after stroke is frequently assessed with clinical scales such as the modified Rankin Scale score (mRS). Days alive and out of hospital at 90 days (DAOH‐90), which measures survival, time spent in hospital or rehabilitation settings, readmission and institutionalization, is an objective outcome measure that can be obtained from large administrative data sets without the need for patient contact. We aimed to assess the comparability of DAOH with mRS and its relationship with other prognostic variables after acute stroke reperfusion therapy. Methods and Results Consecutive patients with ischemic stroke treated with intravenous thrombolysis or endovascular thrombectomy were analyzed. DAOH‐90 was calculated from a national minimum data set, a mandatory nationwide administrative database. mRS score at day 90 (mRS‐90) was assessed with in‐person or telephone interviews. The study included 1278 patients with ischemic stroke (714 male, median age 70 [59–79], median National Institutes of Health Stroke Scale score 14 [9–20]). Median DAOH‐90 was 71 [29–84] and median mRS‐90 score was 3 [2–5]. DAOH‐90 was correlated with admission National Institutes of Health Stroke Scale score (Spearman rho −0.44, P0 was 0.86 (95% CI, 0.84–0.88), mRS score >1 was 0.88 (95% CI, 0.86–0.90) and mRS score >2 was 0.90 (95% CI, 0.89–0.92). Conclusions In patients with stroke treated with reperfusion therapies, DAOH‐90 shows reasonable comparability to the more established outcome measure of mRS‐90. DAOH‐90 can be readily obtained from administrative databases and therefore has the potential to be used in large‐scale clinical trials and comparative effectiveness studies.

Abstract Background The Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long‐term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3‐year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy. Methods Medicaid‐insured or uninsured patients aged 40–64 with stage I–III breast, cervical, colon, or non‐small cell lung cancer within the National Cancer Database (NCDB). A difference‐in‐differences (DID) approach was used to compare changes in TTI (within 60 days) and 3‐year OS between patients in ME states versus nonexpansion (NE) states before (2010–2013) and after (2015–2018) ME. Adjusted DID estimates for TTI and 3‐year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively. Results ME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

Abstract Objective The aims of the study were to (1) characterize the findings of flexible endoscopic evaluation of swallowing (FEES) in stroke patients undergoing mechanical thrombectomy (MT); (2) analyse the screening performance of the Standardized Swallowing Assessment (SSA); and (3) study the impact of FEES‐defined dysphagia on 3‐month outcomes. Methods This single‐centre study was based on a local registry of consecutive acute ischaemic stroke patients undergoing MT during a 1‐year period. Patients received FEES within 5 days of admission regardless of the result of dysphagia screening. We compared baseline demographic and clinical characteristics of patients with and without FEES‐defined dysphagia. We collected 3‐month modified Rankin Scale (mRS) and individual index values of the European Quality of Life 5 Dimensions (EQ‐5D‐iv). Using univariable and multivariable regression analyses we predicted 3‐month outcomes for presence of dysphagia and for FEES‐defined dysphagia severity. Results We included 137 patients with a median age of 74 years, 43.1% were female, median NIHSS was 12 and successful recanalization was achieved in 92.7%. Stroke‐associated pneumonia occurred in 8% of patients. FEES‐defined dysphagia occurred in 81% of patients. Sensitivity of the SSA as a dysphagia screening was 67%. Presence of dysphagia and increasing severity of dysphagia were independently associated with increasing 3‐month mRS score. Increasing dysphagia severity dysphagia was independently associated with lower EQ‐5D‐iv. Interpretation Early FEES‐defined dysphagia occurs in four in every five patients undergoing MT. SSA has a suboptimal dysphagia screening performance. Presence of dysphagia and increasing dysphagia severity predict worse functional outcome and worse health‐related quality‐of‐life.

Societal Impact Statement Various techniques to modify genomes have been developed over the past decades, from molecular cloning to gene editing techniques. What are their applications? What are the key themes discussed by scientists? To answer these questions, we provide a qualitative and quantitative analysis of 14,739 scientific articles published between 1990 to 2022 showing that some themes are constant over time, such as the molecular aspects of genetics and discussions about data and software, while other themes emerged more recently. For example, CRISPR/Cas9 became prominent from 2012 onwards, and applications in agriculture and policy/regulatory implications from 2015 onwards. This mixed method opens up new spaces for dialogue between the natural and social sciences and captures the shifting boundaries of science. Summary The article analyzes publications in the biological sciences concerned with genetic engineering, in particular gene editing, between 1990 and 2022 to examine key and emerging themes. It provides a lexicometric analysis of 14,739 articles, which were subdivided into four periods (1990–2011, 2012–2015, 2016–2018, and 2019–2022). We show that certain themes are constant over time, such as the molecular aspects of genetic engineering techniques and discussions about data and software. Other themes, however, have emerged at specific moments in time: CRISPR/Cas9 became prominent from 2012 onwards and applications in agriculture and policy and regulatory implications from 2015 onwards. We observe, in particular, a semantic shift from genetically modified organisms (GMOs) to crops. The article contributes to debates about the boundaries of science by shedding light on the temporal dynamics of boundary‐work and by showing how the frames of scientific debates can shift to account for the political aspects of science. We conclude that the dialogue between the natural and social sciences can be strengthened by showing that apart from scientometric approaches, there are other methods to analyze “what counts” in science.

Abstract Efforts to limit the impact of the coronavirus disease (COVID‐19) pandemic led to the implementation of public health measures and reallocation of health resources. To investigate trends in blood pressure (BP), hypertension and BMI in the Australian population during the COVID‐19 pandemic, data from publicly accessible health stations were analyzed. Average BP and BMI measured by the SiSU Health Station network in Australia in over 1.6 million health screenings were compared between the years 2018 and 2021. Additionally, paired trajectories for BP and BMI development before and during the COVID‐19 pandemic were calculated. Comparisons between pre‐COVID years and post‐COVID years of 2018 versus 2020, 2019 versus 2020, 2018 versus 2021, and 2019 versus 2021 showed increases in average adjusted systolic BP of 2.0, 1.7, 2.6, and 2.3 mmHg, respectively. Paired analysis of longitudinal data showed an overall increase in the trajectory of systolic BP of 3.2 mmHg between pre‐ and post‐COVID years. The prevalence of hypertension in users of the health stations increased by approximately 25% in the years 2020–2021. Similar trends were seen for BMI. Data from public Australian health stations indicated a strong trend toward higher BP during the COVID‐19 pandemic. At the population level, BP increments have been shown to markedly increase cardiovascular disease risk. Anti‐pandemic measures need to be carefully evaluated in terms of secondary public health effects and health support systems extended to effectively target cardiovascular risk.

Abstract Objective The natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS. Methods MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. Results Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001). Interpretation These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Abstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.

Abstract Environmental DNA (eDNA) data make it possible to measure and monitor biodiversity at unprecedented resolution and scale. As use‐cases multiply and scientific consensus grows regarding the value of eDNA analysis, public agencies have an opportunity to decide how and where eDNA data fit into their mandates. Within the United States, many federal and state agencies are individually using eDNA data in various applications and developing relevant scientific expertise. A national strategy for eDNA implementation would capitalize on recent scientific developments, providing a common set of next‐generation tools for natural resource management and public health protection. Such a strategy would avoid patchwork and possibly inconsistent guidelines in different agencies, smoothing the way for efficient uptake of eDNA data in management. Because eDNA analysis is already in widespread use in both ocean and freshwater settings, we focus here on applications in these environments. However, we foresee the broad adoption of eDNA analysis to meet many resource management issues across the nation because the same tools have immediate terrestrial and aerial applications.

Abstract Introduction Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)‐based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG‐based ART on gestational weight gain (GWG) in sub‐Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes. Methods We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri‐urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study‐measured at 24–28 (baseline) and 33–38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z‐scores were generated using the INTEGROWTH‐21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z‐score with adverse birth outcomes were assessed using multivariable linear or log‐binomial regression. Results Among 292 participants (48% WHIV), median age was 29 years (IQR, 25–33), median pre‐pregnancy body mass index (BMI) was 31 kg/m2 (IQR, 26–36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12–0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p4000 g (RR = 2.18 95% CI 1.18, 4.01). Conclusions Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub‐Saharan Africa are urgently needed.

Abstract Glaciers and ice streams flowing over sediment beds commonly have a layer of ice‐rich debris adhered to their base, known as a “frozen fringe,” but its impact on basal friction is unknown. We simulated basal slip over granular beds with a cryogenic ring shear device while ice infiltrated the bed to grow a fringe, and measured the frictional response under different effective stresses and slip speeds. Frictional resistance increased with increasing slip speed until it plateaued at the frictional strength of the till, closely resembling the regularized Coulomb slip law associated with clean ice over deformable beds. We hypothesize that this arises from deformation in a previously unidentified zone of weakly frozen sediments at the fringe's base, which is highly sensitive to temperature and stress gradients. We show how a rheologic model for ice‐rich debris coupled with the thermomechanics of fringe growth can account for the regularized Coulomb behavior.

Abstract Direct recycling is a novel approach to overcoming the drawbacks of conventional lithium‐ion battery (LIB) recycling processes and has gained considerable attention from the academic and industrial sectors in recent years. The primary objective of directly recycling LIBs is to efficiently recover and restore the active electrode materials and other components in the solid phase while retaining electrochemical performance. This technology's advantages over traditional pyrometallurgy and hydrometallurgy are cost‐effectiveness, energy efficiency, and sustainability, and it preserves the material structure and morphology and can shorten the overall recycling path. This review extensively discusses the advancements in the direct recycling of LIBs, including battery sorting, pretreatment processes, separation of cathode and anode materials, and regeneration and quality enhancement of electrode materials. It encompasses various approaches to successfully regenerate high‐value electrode materials and streamlining the recovery process without compromising their electrochemical properties. Furthermore, we highlight key challenges in direct recycling when scaled from lab to industries in four perspectives: (1) battery design, (2) disassembling, (3) electrode delamination, and (4) commercialization and sustainability. Based on these challenges and changing market trends, a few strategies are discussed to aid direct recycling efforts, such as binders, electrolyte selection, and alternative battery designs; and recent transitions and technological advancements in the battery industry are presented.

Abstract The 2020 State of the World's Plants and Fungi report revealed that two in five plant species are threatened with extinction. Despite their diverse ecosystem services and myriad human uses, plants receive a fraction of the conservation resources directed at animal taxa. Several existing frameworks—including International Union for Conservation of Nature (IUCN) Specialist Groups, the American Public Gardens Association Plant Collections Network, and the Center for Plant Conservation National Collection of Endangered Plants—have spurred conservation action, but there remains an urgent need to scale up conservation efforts for the world's plants. Here, a new approach to coordinated conservation action for plant taxa is described: the Global Conservation Consortia (GCC). GCC catalyze institutions and experts to collaboratively develop and implement comprehensive strategies to prevent extinction of threatened plant groups. This review focuses on three tree‐focused, U.S.‐led consortia: cycads, magnolias, and oaks, but the GCC framework is applicable to other taxonomic groups. This review covers consortia design and implementation, provides conservation action case studies, and shares preliminary successes and challenges as this new and exciting approach to conservation is developed.