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Abstract Objective Epileptogenesis is linked to neuroinflammation. We hypothesized that local heat production caused by neuroinflammation can be visualized non‐invasively in vivo via brain magnetic resonance spectroscopic imaging (MRSI) and MRSI‐thermometry (MRSI‐t) and that there is a relationship in patients with temporal lobe epilepsy (TLE) between MRSI‐t and brain metabolites choline and myo‐inositol and between neuroimaging and cellular and serum biomarkers of inflammation. Methods Thirty‐six (36) participants, 18 with temporal lobe epilepsy (13 females) and 18 age‐matched healthy controls (nine females), were enrolled prospectively and underwent MRSI/MRSI‐t; TLE participants also provided blood samples. Temperature was measured using creatine as a reference metabolite. Analysis of Functional NeuroImages 3dttest++ tool was used to analyze voxel‐level group differences in temperature, choline, and myo‐inositol. Associations with immune cell subsets, cytokines, and chemokines related to inflammation were quantified using correlation coefficients with significant relationships as noted. Results Patients with TLE showed elevated temperature, choline, and myo‐inositol in the temporal lobes. Higher brain temperature was associated with higher levels of cytokines and chemokines, including GM‐CSF, TNF, IL‐1β, and IL − 12p70, and lower frequency of immune cells including CD3+ T‐cells, CD4+ T‐cells, CD8+ T‐cells, and classical monocytes. Higher choline was associated with higher levels of the cytokines including LT‐α, IL‐13, and IL‐4, and higher myo‐inositol was associated with a higher frequency of CD4+ T‐cell and CD19+ B‐cell subsets and higher levels of cytokines and chemokines including LT‐α, IL‐13, and CCL3. Significance This study, for the first time, showed that in temporal lobes of patients with TLE temperature and metabolite changes correlate with cellular and serum biomarkers of inflammation. Our results provide support for further development of MRSI‐t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool. Plain Language Summary Neuroinflammation is associated with excessive heat production which can be visualized with magnetic resonance spectroscopic imaging and thermometry (MRSI‐t). We prospectively investigated the relationship between MRSI‐t and cellular and serum measures of peripheral inflammation in patients with temporal lobe epilepsy (TLE); we compared the results of MRSI‐t in patients with TLE to healthy controls. We showed a relationship between the temperature elevations in TLE and elevations of various measures of peripheral inflammation. Our results support further development of MRSI‐t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool.

Abstract Aims Concentrations of high‐sensitivity cardiac troponin T (hs‐cTnT) are frequently elevated in stable patients with confirmed muscle dystrophies. However, sparse information is available on the interpretation of serial concentration changes. Methods Hs‐cTnT was collected in 35 stable outpatients with confirmed skeletal muscle dystrophies at 0 and 1 h and after 6–12 months during scheduled outpatient visits. We simulated the effectiveness of the European Society of Cardiology (ESC) 0/1 h algorithm and assessed biological variation at 6–12 months using two established methods: reference change value (RCV) and minimal important difference (MID). Results Median baseline hs‐cTnT concentrations were 34.4 ng/L [inter‐quartile range (IQR): 17.5–46.2], and values > 99th percentile upper limit of normal were present in 34 of 35 patients. All patients were stable without cardiovascular adverse events during a follow‐up of 6.6 months (IQR: 6–7). Median concentration change was 1.9 ng/L (IQR: 0.7–3.2) and 0.8 ng/L (IQR: 0–7.0) at 60 min and 6–9 months, respectively. Applying the criteria of the ESC 0/1 h algorithm for triage of suspected acute coronary syndrome (ACS) showed poor overall effectiveness of baseline hs‐cTnT values. No patient would qualify for rule‐out based on hs‐cTnT less than the limit of detection, whereas five cases would qualify for rule‐in based on hs‐cTnT ≥ 52 ng/L. Biological variabilities at 6–12 months per MID and RCV were 1.2 ng/L [95% confidence interval (CI): 0.7–2.1] and 28.6% (95% CI: 27.9–29.6), respectively. A total of 8 (22.9%) and 25 (71.4%) cases exceeded the biological variation range, suggesting some additional myocardial damage. Conclusions The high prevalence of elevated hs‐cTnT could negatively impact the effectiveness of rule‐out and rule‐in strategies based on a single hs‐cTnT value. Knowledge of the physiological and biological variation of hs‐cTnT after 6–12 months is helpful to detect the progression of cardiac involvement or to search for cardiac complications including but not limited to arrhythmias that may trigger acute or chronic myocardial damage.

Abstract Precipitation channelled down tree stems (stemflow) or into drip points of ‘throughfall’ beneath trees results in spatially concentrated inputs of water and chemicals to the ground. Currently, these flows are poorly characterised due to uncertainties about which branches redirect rainfall to stemflow or throughfall drip points. We introduce a graph theoretic algorithm that ‘prunes’ quantitative structural models of trees (derived from terrestrial LiDAR) to identify branches contributing to stemflow and those contributing to throughfall drip points. To demonstrate the method's utility, we analysed two trees with similar canopy sizes but contrasting canopy architecture and rainfall partitioning behaviours. For both trees, the branch ‘watershed’ area contributing to stemflow (under conditions assumed to represent moderate precipitation intensity) was found to be only half of the total ground area covered by the canopy. The study also revealed significant variations between trees in the number and median contribution areas of modelled throughfall drip points (69 vs. 94 drip points tree−1, with contributing projected areas of 28.6 vs. 7.8 m2 tree−1, respectively). Branch diameter, surface area, volumes and woody area index of components contributing to stemflow and throughfall drip points may play a role in the trees' differing rainfall partitioning behaviours. Our pruning algorithm, enabled by the proliferation of LiDAR observations of canopy structure, promises to enhance studies of canopy hydrology. It offers a novel approach to refine our understanding of how trees interact with rainfall, thereby broadening the utility of existing LiDAR data in environmental research.

Abstract Over the past five decades, a large number of wild animals have been individually identified by various observation systems and/or temporary tracking methods, providing unparalleled insights into their lives over both time and space. However, so far there is no comprehensive record of uniquely individually identified animals nor where their data and metadata are stored, for example photos, physiological and genetic samples, disease screens, information on social relationships. Databases currently do not offer unique identifiers for living, individual wild animals, similar to the permanent ID labelling for deceased museum specimens. To address this problem, we introduce two new concepts: (1) a globally unique animal ID (UAID) available to define uniquely and individually identified animals archived in any database, including metadata archived at the time of publication; and (2) the digital ‘home’ for UAIDs, the Movebank Life History Museum (MoMu), storing and linking metadata, media, communications and other files associated with animals individually identified in the wild. MoMu will ensure that metadata are available for future generations, allowing permanent linkages to information in other databases. MoMu allows researchers to collect and store photos, behavioural records, genome data and/or resightings of UAIDed animals, encompassing information not easily included in structured datasets supported by existing databases. Metadata is uploaded through the Animal Tracker app, the MoMu website, by email from registered users or through an Application Programming Interface (API) from any database. Initially, records can be stored in a temporary folder similar to a field drawer, as naturalists routinely do. Later, researchers and specialists can curate these materials for individual animals, manage the secure sharing of sensitive information and, where appropriate, publish individual life histories with DOIs. The storage of such synthesized lifetime stories of wild animals under a UAID (unique identifier or ‘animal passport’) will support basic science, conservation efforts and public participation.

Abstract The storage of organic carbon in the soils of salt marshes and other coastal blue carbon ecosystems has gained considerable attention by the scientific community for more than a decade now, while the relevance and mechanisms of soil inorganic carbon accumulation remain poorly understood. Using long‐term annual accretion monitoring over 17 years in N = 50 permanent plots distributed across a 1050‐ha salt‐marsh complex of the European Wadden Sea, we identified clear relationships between salt‐marsh vertical growth rates and the soil densities of inorganic and organic carbon. Specifically, we demonstrate a strong positive correlation between vertical accretion and inorganic carbon density while observing a strong negative correlation between vertical accretion and organic carbon density. This decoupling observed between inorganic and organic soil carbon stocks was governed by plant community composition and associated plant traits, which controlled sedimentation processes.

Abstract A bottleneck in the development of new anti‐cancer drugs is the recognition of their mode of action (MoA). Metabolomics combined with machine learning allowed to predict MoAs of novel anti‐proliferative drug candidates, focusing on human prostate cancer cells (PC‐3). As proof of concept, 38 drugs are studied with known effects on 16 key processes of cancer metabolism, profiling low molecular weight intermediates of the central carbon and cellular energy metabolism (CCEM) by LC‐MS/MS. These metabolic patterns unveiled distinct MoAs, enabling accurate MoA predictions for novel agents by machine learning. The transferability of MoA predictions based on PC‐3 cell treatments is validated with two other cancer cell models, i.e., breast cancer and Ewing's sarcoma, and show that correct MoA predictions for alternative cancer cells are possible, but still at some expense of prediction quality. Furthermore, metabolic profiles of treated cells yield insights into intracellular processes, exemplified for drugs inducing different types of mitochondrial dysfunction. Specifically, it is predicted that pentacyclic triterpenes inhibit oxidative phosphorylation and affect phospholipid biosynthesis, as confirmed by respiration parameters, lipidomics, and molecular docking. Using biochemical insights from individual drug treatments, this approach offers new opportunities, including the optimization of combinatorial drug applications.

ABSTRACT Hyperactivation of the hypothalamic‐pituitary‐adrenal (HPA) axis response can result in anxiety and other neuropsychiatric disorders and effective therapeutics are needed to mitigate this maladaptive response. Here we examined the effects of Teneurin C‐terminal Associated Peptide (TCAP)‐1, a peptide known to inhibit corticotropin releasing factor (CRF)‐mediated stress, on the physiological expression of stress, and whether the effects of TCAP‐1 were dependent on the route of administration. We first examined whether subcutaneous administration of TCAP‐1 influenced tube restraint stress‐induced corticosterone (CORT) increases in both male mice and rats. Using a similar model, we further examined the efficacy and time course of intranasal TCAP‐1. Results showed that subcutaneous TCAP‐1 administration attenuated the expression of the physiological manifestation of stress in male mice and rats, and that intranasal TCAP‐1 delivered prophylactically is effective at attenuating stress‐induced CORT increases in male rats. These data indicate that TCAP‐1 delivered though non‐invasive routes of administration could have potential as a clinically relevant anxiolytic.

Abstract Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML‐exclusive, non‐HSPC‐expressed cell‐surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface‐directed immunotherapy in this disease setting, time‐limited combined immune‐targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single‐chain variable fragment‐based bispecific T‐cell engaging and activating antibody directed against CD3 on T‐cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117‐positive healthy human HSPCs, AML cell lines and patient‐derived AML blasts in the presence of T‐cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117‐expressing leukemia cells and human T‐cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117‐positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117‐expressing leukemia cells and HSPCs prior to HSCT.

Abstract While surgical resection is a mainstay of cancer treatment, many tumors are unresectable due to stage, location, or comorbidities. Ablative therapies, which cause local destruction of tumors, are effective alternatives to surgical excision in several settings. Ethanol ablation is one such ablative treatment modality in which ethanol is directly injected into tumor nodules. Ethanol, however, tends to leak out of the tumor and into adjacent tissue structures, and its biodistribution is difficult to monitor in vivo. To address these challenges, this study presents a cutting‐edge technology known as Light‐Activatable Sustained‐Exposure Ethanol Injection Technology (LASEIT). LASEIT comprises a three‐part formulation: (1) ethanol, (2) benzoporphyrin derivative, which enables fluorescence‐based tracking of drug distribution and the potential application of photodynamic therapy, and (3) ethyl cellulose, which forms a gel upon injection into tissue to facilitate drug retention. In vitro drug release studies showed that ethyl cellulose slowed the rate of release in LASEIT by 7×. Injections in liver tissues demonstrated a 6× improvement in volume distribution when using LASEIT compared to controls. In vivo experiments in a mouse pancreatic cancer xenograft model showed LASEIT exhibited significantly stronger average radiant efficiency than controls and persisted in tumors for up to 7 days compared to controls, which only persisted for less than 24 h. In summary, this study introduced LASEIT as a novel technology that enabled real‐time fluorescence monitoring of drug distribution both ex vivo and in vivo. Further research exploring the efficacy of LASEIT is strongly warranted.

Objective T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well‐characterized cohort of patients with SSc. Methods Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t‐distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays. Results The frequencies of PD‐1highCXCR5+ Tfh cells and PD‐1highCXCR5− Tph cells were similar in patients with SSc and controls. t‐distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD‐1highCXCR5− cells distinguished by expression of HLA–DR and inducible costimulator (ICOS). Among PD‐1highCXCR5− cells, only the HLA–DR+ICOS− cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA–DR+ICOS− PD‐1highCXCR5− cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA–DR+ICOS−PD‐1highCXCR5− cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc. Conclusion Among PD‐1highCXCR5− T cells, a subset of HLA–DR+ICOS− cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.

Abstract Emotions are short, intuitive mental processes that are important components of people's cognitions. They can influence attitudes (i.e. positive or negative evaluations of objects), and they are involved in decision‐making processes. In the context of human‐wildlife coexistence, mostly emotional dispositions have been studied (i.e. people's decontextualized, stable tendencies to react in a certain way towards wildlife), in contrast to emotional states (i.e. quick reactions elicited in specific contexts), which have been overlooked. This limits our understanding of emotional states and the role of emotional diversity in shaping attitudes towards wildlife species. Here, we quantified emotional states elicited by context‐specific wolf encounters featured in a set of YouTube videos. We conducted a social survey in rural populations of 24 randomly selected cities in France (n = 795) to (i) quantify emotional diversity and (ii) test the relationship between emotional states and attitudes towards wolves, accounting for individual and regional factors. We found that emotional states that were most expressed across the six contexts of encounter were surprise, interest and fear, in this order. Emotional diversity was highly context‐specific, with significantly different emotional identity, dispersion and extremization across the six contexts of encounters. Most variance in attitudes was explained by emotional factors alone (28%) and the best model including all three groups of predictors (emotional, individual and regional factors) explained 57% of the variance. The strongest effects of emotional states on attitudes were those of anger and joy. Fear had only half the effect of joy on attitudes. Synthesis and applications: Our results highlight the importance and context‐specificity of emotional diversity for human‐carnivore coexistence. Complementary to previous studies focusing on single emotions and on decontextualized emotional dispositions, quantifying diverse, context‐dependent emotional states can be helpful to improve decision‐making in three different ways: (i) address relevant contexts triggering anger, which is a feeling rooted in perceived injustice, (ii) reduce emotional biases involving fear of carnivores given the extremely low probability of risks to human life and (iii) promote positive emotions like joy to better reflect costs and benefits of sharing landscapes with large carnivores. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Vegetation health forecasting (NDVI as a proxy) informs decision‐makers about the end of season crop yield productivity but is not well‐documented. This study tests improvements in vegetation health forecasting by developing a data‐driven Dynamic Agricultural Productivity Indicator (DAPI), which simultaneously incorporates satellite‐based root zone soil moisture (RZSM) and satellite‐based NDVI data. RZSM is estimated via data assimilation of satellite based SMAP SM dataset. We employ the proposed DAPI forecast across four cropland types in the CONUS, including corn, cotton, soybeans, and wheat. Results demonstrate superior performance of the DAPI forecasts compared to climatology‐based NDVI forecasts, with the largest improvements in water‐limited regions. DAPI shows particularly good performance during hydrologic disturbances such as floods and droughts. To this end, the DAPI approach is useful in estimating future vegetation health for identifying potential food‐insecure areas, predicting crop price changes, and projecting expected commodities market trends.

Abstract The ability to accurately measure drug‐target interaction is critical for the discovery of new therapeutics. Classical pharmacological bioassays such as radioligand or fluorescent ligand binding assays can define the affinity or Kd of a ligand for a receptor with the lower the Kd, the stronger the binding and the higher the affinity. However, in many drug discovery laboratories today, the target of interest if often artificially upregulated by means of transfection to modify the host cell's genetic makeup. This then potentially invalidates the assumptions of classical pharmacology affinity calculations as the receptor of interest is no longer at normal physiological densities. The CXCR4 receptor is expressed on many different cancer cell types and is associated with metastasis and poor prognosis. Therefore, the CXCR4 receptor is a desirable target for novel therapeutics. In this study, we explore the applicability of the newly developed fluorescently tagged CXCR4 antagonists, IS4‐FAM as an investigative tool to study CXCR4 affinity and competitive antagonism in native, non‐transfected cancer cells using confocal microscopy and flow cytometry. IS4‐FAM directly labels CXCR4 in several cell lines including high CXCR4 expressing SK‐MEL‐28 (malignant melanoma) and PC3 (metastatic prostate cancer) and lower CXCR4 expressing THP‐1 (acute monocytic leukemia) and was competitive with the established CXCR4 antagonist, AMD3100. This highlights the potential of IS4‐FAM as a pharmacological tool for drug discovery in native cells lines and tissues.

Background Higher cardiac troponin is associated with worse outcomes in patients with acute heart failure. The significance of repeat measurements over hours remains unclear. We assessed whether a repeat measurement and the Δ between measurements of high‐sensitivity cardiac troponin I (hs‐cTnI) were associated with outcomes in hypervolemic patients with acute heart failure without acute coronary syndrome. Methods and Results We analyzed 582 individuals from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase‐Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) with hs‐cTnI measured ≤12 hours from admission and repeated ≤6 hours thereafter. Associations between hs‐cTnI levels and their Δ with short‐term (death, intensive care unit admission, receipt of inotropes, or positive pressure ventilation during hospitalization) and long‐term (death or heart failure readmission within 1 year) outcomes were assessed. The average age was 69±13 years, 62% were men, 65% were White, 46% had coronary artery disease, and 22% had chest pain. Median hs‐cTnI levels were 27 (interquartile range [IQR], 13–62) ng/L initially and 28 (IQR, 14–68) ng/L subsequently, with a Δ of 0 [IQR, −2 to 4] ng/L over 3.4±1 hours. Only the second measurement was associated with short‐term outcomes (odds ratio, 1.14 per 2‐fold higher [95% CI, 1.02–1.28]). Both individual measurements and the Δ were associated with long‐term outcomes (hazard ratios, 1.09, 1.12, and 1.16 for first, second, and Δ, respectively). Associated risk for the first and second measurements were not constant over the year but highest early after being measured and decreased over 1 year. Conclusions Repeat measurements of hs‐cTnI over hours can identify individuals with acute heart failure without acute coronary syndrome at risk for short‐ and long‐term outcomes.

Abstract Economic losses due to hailstorms across US corn fields occur every year. Hailstorms result in leaf defoliation, decreasing photosynthetic area and impairing carbon assimilation and crop yield for all corn (Zea mays L.) development stages. However, more attention is often given to stand reductions rather than damage to stems or leaf defoliation. During the 2014 growing season, a natural hail event affected many areas of eastern Nebraska. Twelve affected corn fields were surveyed and included in this study. An injury score scale (1–5) was developed based on various injury and severity levels before the V6 (6‐leaf corn growth stage) (six‐collared leaves). Scores were assigned to affected fields approximately 10–15 days after the hailstorm. At the end of the growing season, ears were harvested, and grain yield per plant was determined. The highest grain yield (p

Abstract Worldwide, trees are colonizing rangelands with high conservation value. The introduction of trees into grasslands and shrublands causes large‐scale changes in ecosystem structure and function, which have cascading impacts on ecosystem services, biodiversity, and agricultural economies. Satellites are increasingly being used to track tree cover at continental to global scales, but these methods can only provide reliable estimates of change over recent decades. Given the slow pace of tree cover expansion, remote sensing techniques that can extend this historical record provide critical insights into the magnitude of environmental change. Here, we estimate conifer expansion in rangelands of the northern Great Plains, United States, North America, using historical aerial imagery from the mid‐20th century and modern aerial imagery. We analyzed 19.3 million hectares of rangelands in Montana, USA, using a convolutional neural network (U‐Net architecture) and cloud computing to detect tree features and tree cover change. Our bias‐corrected results estimate 3.0 ± 0.2 million hectares of conifer tree cover expansion in Montana rangelands, which accounts for 15.4% of the total study area. Overall accuracy was >91%, but the producer's accuracy was lower than the user's accuracy (0.60 vs. 0.88) for areas of tree cover expansion. Nonetheless, the omission errors were not spatially clustered, suggesting that the method is reliable for identifying the regions of Montana where substantial tree expansion has occurred. Using the model results in conjunction with historical and modern imagery allows for effective communication of the scale of tree expansion while overcoming the recency effect caused by shifting environmental baselines.

Tyrosine‐protein kinase (janus kinase; JAK)–signal transducer and activator of transcription (STAT) signaling plays a pivotal role in the development of myeloproliferative neoplasms (MPNs). Treatment with the potent JAK1/JAK2‐specific inhibitor, ruxolitinib, significantly reduces tumor burden; however, ruxolitinib treatment does not fully eradicate the malignant clone. As the molecular basis for the disease persistence is not well understood, we set out to gain new insights by generating ruxolitinib‐resistant cell lines. Surprisingly, these cells harbor a 45 kDa JAK2 variant (FERM‐JAK2) consisting of the N‐terminal FERM domain directly fused to the C‐terminal kinase domain in 80% of sublines resistant to ruxolitinib. At the molecular level, FERM‐JAK2 is able to directly bind and activate STAT5 in the absence of cytokine receptors. Furthermore, phosphorylation of activation‐loop tyrosines is dispensable for FERM‐JAK2‐mediated STAT5 activation and cellular transformation, in contrast to JAK2‐V617F. As a result, FERM‐JAK2 is highly resistant to several ATP‐competitive JAK2 inhibitors, whereas it is particularly sensitive to HSP90 inhibition. A murine model of FERM‐JAK2 leukemogenesis showed an accelerated MPN phenotype with pronounced splenomegaly. Notably, most current protocols for the monitoring of emerging JAK variants are unable to detect FERM‐JAK2, highlighting the urgent need for implementing next‐generation sequencing approaches in MPN patients receiving ruxolitinib.

Abstract Inflammation is one of the suggested pathways linking exposure to neighbourhood air pollution and greenspace to psychological distress. Yet, inflammation has not been tested formally as a mediating factor in an adult human sample. Using data from 6813 adults participating in Understanding Society, the present study examines longitudinally the joint role of the two neighbourhood‐level exposures in psychological distress and the mediating role of inflammation. Annual concentrations of nitrogen dioxide and availability of greenspace in participants' neighbourhoods across England and Wales were examined. Psychological distress was measured with the General Health Questionnaire. Inflammation was assessed with C‐reactive protein and fibrinogen. A structural equation model path analysis showed that, in fully adjusted models, an increase in the amount of greenspace in one's neighbourhood was related to lower psychological distress 4 years later, but inflammation did not mediate this relationship. Neighbourhood‐level air pollution, specifically nitrogen dioxide, was not associated with psychological distress. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Marine scientific trawl surveys are commonly used to assess the distribution and population size of fisheries‐related species, yet the method is effort‐intensive and can be environmentally destructive. Sequencing environmental DNA (eDNA) from water samples can reveal the presence of organisms in a community without capturing them; however, we expect the detectability of taxa to differ between eDNA and trawl surveys, and understanding how species traits and population variables contribute to detection differences can help calibrate our expectations from each form of sampling. Here, we coupled eDNA metabarcoding and capture trawl surveys in British Columbia, Canada, to examine species traits that explain recurrent differences in detectability between the two methods, including habitat, body size, and biomass. At the regional scale, 17 of 23 fish species (74%) captured by the trawl were detected by eDNA metabarcoding, and 39 additional species were detected by eDNA sampling only. We found that eDNA metabarcoding disproportionately detected trawl‐caught species with greater local biomass (i.e., greater biomass in the adjacent trawl). Fish detected only in eDNA had a greater range of body lengths and a broader range of habitat preferences outside the trawls' target size and sampling areas. Our results suggest that with our level of sampling, eDNA metabarcoding can adequately recapitulate detection of fish communities detected by trawl surveys, but with a bias toward fish of high population biomass and greater inclusion of fish from outside the trawled area.

Abstract Objectives The aim of the present study was to follow the daily course of patients with olfactory dysfunction and healthy controls and to assess (i) how many times a day, (ii) at which time, and (iii) in which aspect of daily life participants are conscious about their sense of smell. Methods In this longitudinal study, 49 patients with smell loss and 30 healthy participants were enrolled. Olfactory function was assessed using the Sniffin’ Sticks. All participants received paper diaries designed for a 14‐day period, featuring 12 rows representing 12 daily hours and six columns for various daily life aspects. They were instructed to mark their awareness of smell by indicating the relevant row and column in the diary. Following the return of the diaries, a second olfactory test was conducted within the patient group. Results On average, patients were consciously aware of their sense of smell around 8 times daily, while healthy participants noted it about 6.5 times a day. Both groups primarily focused on their sense of smell during activities related to “eating,” followed by considerations in “social life” and “personal hygiene.” Interestingly, distinct patterns emerged: patients peaked in awareness at 8 a.m. and 7 p.m., whereas healthy individuals showed peaks at 6 a.m., 12 p.m., and 7 p.m. Despite regular diary use, we observed no improvement in patients' olfactory function or related quality of life. Conclusion The olfactory diary is a valuable tool unveiling individual smell awareness patterns in patients with smell loss, aiding in counseling and patient management. Level of Evidence 4

Background Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. Methods and Results Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross‐sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new‐onset obesity, hypertension, type 2 diabetes, CVD, and all‐cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR‐193b‐3p, miR‐122‐5p, miR‐365a‐3p, miR‐194‐5p, miR‐192‐5p, and miR‐193a‐5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR‐193b‐3p, miR‐194‐5p, and miR‐193a‐5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all‐cause mortality in the FHS. Conclusions These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Background Currently, no clear impact of sex on short‐ and long‐term survival following transcatheter edge‐to‐edge mitral valve repair (TEER) is evident, although no data are available on postprocedural life expectancy. Our aim was to assess sex‐specific differences in outcomes of patients with mitral regurgitation (MR) treated by TEER. Methods and Results Short‐term and 5‐year outcomes in men and women undergoing TEER between 2011 and 2018 who were included in the large, multicenter, real‐world MitraSwiss registry were analyzed. Outcomes were compared stratified by sex and according to MR cause (primary versus secondary). The impact of TEER on postprocedural life expectancy was estimated by relative survival analysis. Among 1142 patients aged 60 to 89 years, 39.8% were women. They were older, with fewer cardiovascular risk factors and lower functional capacity compared with men. Thirty‐day mortality was higher in men than in women (3.3% versus 1.1%; odds ratio, 3.16 [95% CI, 1.16–10.7]; P=0.020). Five‐year survival was comparable in both sexes (adjusted hazard ratio for 5‐year mortality in men, 1.14 [95% CI, 0.90–1.44], P=0.275). Both men and women with either primary or secondary MR showed similar clinical efficacy over time. TEER provided high relative survival estimates among all groups, and fully restored predicted life expectancy in women with primary MR (5‐year relative survival estimate, 97.4% [95% CI, 85.5–107.0]). Conclusions TEER is not associated with increased short‐term mortality in women, whereas 5‐year outcomes are comparable between sexes. Moreover, TEER completely restored normal life expectancy in women with primary MR. A residual excess mortality persists in secondary MR, independently of sex.

Background The determinants and prognostic value of high‐sensitivity cardiac troponin T (hs‐cTnT) among patients with a systemic right ventricle are largely unknown. Methods and Results Ninety‐eight patients from the randomized controlled SERVE (Effect of Phosphodiesterase‐5 Inhibition With Tadalafil on Systemic Right Ventricular Size and Function) trial were included. The correlation between baseline hs‐cTnT concentrations and biventricular volumes and function quantified by cardiac magnetic resonance or cardiac multirow detector computed tomography was assessed by adjusted linear regression models. The prognostic value of hs‐cTnT was assessed by adjusted Cox proportional hazards models, survival analysis, and concordance statistics. The primary outcome was time to the composite of clinically relevant arrhythmia, hospitalization for heart failure, or all‐cause death. Median age was 39 (interquartile range, 32–48) years, and 32% were women. Median hs‐cTnT concentration was 7 (interquartile range, 4–11) ng/L. Coefficients of determination for the relationship between hs‐cTnT concentrations and right ventricular end‐systolic volume index and right ventricular ejection fraction (RVEF) were +0.368 (P=0.046) and −0.381 (P=0.018), respectively. The sex‐ and age‐adjusted hazard ratio for the primary outcome of hs‐cTnT at 2 and 4 times the reference level (5 ng/L) were 2.89 (95% CI, 1.14–7.29) and 4.42 (95% CI, 1.21–16.15), respectively. The prognostic performance quantified by the concordance statistics for age‐ and sex‐adjusted models based on hs‐cTnT, right ventricular ejection fraction, and peak oxygen uptake predicted were comparable: 0.71% (95% CI, 0.61–0.82), 0.72% (95% CI, 0.59–0.84), and 0.71% (95% CI, 0.59–0.83), respectively. Conclusions Hs‐cTnT concentration was significantly correlated with right ventricular ejection fraction and right ventricular end‐systolic volume index in patients with a systemic right ventricle. The prognostic accuracy of hs‐cTnT was comparable to that of right ventricular ejection fraction and peak oxygen uptake predicted. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03049540.

Background Mechanical thrombectomy is established for large‐vessel occlusions in acute ischemic stroke, but the potential role in distal vessel occlusions of medium arteries is less well established. Such medium or distal arterial segments have not been assessed with respect to thrombectomy devices used during endovascular therapy. We conducted an analysis of arterial size, segmental anatomy, and stent‐retriever device performance with respect to vessel size during thrombectomy. Methods The STRATIS registry angiography core laboratory adjudicated the exact location of the occlusion, proximal, and distal device deployment, relationship to arterial bifurcations, and anatomic nomenclature. Arterial diameters were measured at all these sites. Statistical analyses examined the relationship between vessel and stent size, and arterial recanalization using expanded Thrombolysis in Cerebral Infarction reperfusion score. Results Overall, 665 patients with stroke were included following thrombectomy using various Solitaire device sizes, including Solitaire 4×40, Solitaire 6×30, Solitaire 4×20, Solitaire 6×20, and Solitaire 4×15. Arterial diameter at the occlusion site was a median of 2.17 mm (interquartile range [IQR], 1.88–2.60 mm) in the distal M1, 1.67 mm (IQR, 1.47–2.06 mm) in the proximal M2 middle cerebral artery, 1.50 mm (IQR, 1.15–1.61 mm) in the distal M2 middle cerebral artery, 1.24 mm (IQR, 1.11–1.24 mm) in the M3 middle cerebral artery, and 1.88 mm (IQR, 1.49–1.94 mm) in the P1 posterior cerebral artery. Expanded Thrombolysis in Cerebral Infarction 2b to 3 reperfusion was achieved in all M3 or P1 segment occlusions. The rate of first‐pass recanalization was significantly higher in patients with medium (0.75–2 mm) versus large (>2 mm) vessel occlusion (69.5% versus 57.1%; P = 0.003). Conclusion Considerable overlap was noted between arterial sizes at occlusion sites carrying different segmental arterial nomenclature or vessel names. Substantial reperfusion may be achieved with currently available mechanical thrombectomy devices in medium arteries.

Background Subarachnoid hemorrhage (SAH) associated with vessel injury during endovascular therapy for acute ischemic stroke is a known complication. Arterial anatomy may predispose to increased risk of SAH and technical safety, yet factors such as clot location, arterial size, and tortuosity have not been explored. We examined these anatomic factors with respect to SAH during thrombectomy. Methods Arterial anatomy at the site of occlusion and mechanical thrombectomy during device deployment was detailed by the STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) core laboratory. Luminal diameters, arterial branching, and segmental tortuosity were measured. Arterial tortuosity was quantified using the distance factor metric. Statistical analyses included descriptive variables of arterial anatomy, with univariable and multivariable modeling to predict SAH. Results Arterial tortuosity in each segment from the proximal cerebral arteries to the site of occlusion was quantified in 790 subjects treated with mechanical thrombectomy in STRATIS. Cumulative arterial tortuosity to the site of vessel occlusion was greater in distal lesions. SAH was clearly linked with more distal thrombectomy (P = 0.02), occurring in 19.0% of distal M2, 16.7% of M3, 7.3% of distal M1, 5.8% of proximal M2, 2.4% of distal internal carotid artery, and 2.1% of proximal M1. In multivariable analysis after adjusting for arterial diameter at the site of occlusion, arterial tortuosity was a significant predictor of SAH (upper tertile versus 1: odds ratio, 3.08 [95% CI, 1.04–9.09]; P = 0.04), while arterial diameter was unrelated to SAH (P = 0.30) when accounting for tortuosity. Conclusion This novel analysis of arterial tortuosity and angiographic anatomy during mechanical thrombectomy establishes tortuosity as a determinant of SAH, providing insight for future techniques and innovative device designs.

Abstract Objective To examine the safety and efficacy of prostatic urethral lift (PUL) in acute urinary retention (AUR) patients within a controlled (PULSAR) and real‐world setting (Real‐World Retrospective study). Materials and methods PULSAR was a 12‐month prospective study of PUL in AUR patients (n = 51) performed at six centres in the United Kingdom; enrolled BPH patients aged ≥50 years, with prostate volume of ≤100 cc. AUR was defined as being catheter dependent with at least one prior failed trial without catheter (TWOC) while on an alpha‐blocker. RWR consisted of 3226 consecutive PUL patients across 22 international sites treated between July 2017 and March 2020; 469 of whom were in urinary retention (RWRr), that is, catheter‐dependent at the time of their procedure. Symptom response, uroflow and catheter independence rates were compared between PULSAR and RWRr subjects. A logistical regression model was constructed to evaluate patient baseline and dynamic factors predicting success after the procedure. Results Seventy‐three percent of PULSAR subjects were catheter independent and free from surgical reintervention at 12 months post‐PUL. Success was associated with higher voiding efficiency during the perioperative period. Slightly higher catheter‐independent rates (80%) were seen in RWRr patients; variables that influenced success included age

Abstract Objective Epilepsy and depression share neurobiological origins, and evidence suggests a possible bidirectional relationship that remains poorly understood. This exploratory, cross‐sectional study aimed to investigate this relationship by employing magnetic resonance spectroscopic imaging (MRSI) and thermometry (MRSI‐t) in patients with temporal lobe epilepsy (TLE) with comorbid depressive symptoms and control participants. This is the first study to combine MRSI and MRSI‐t to examine brain temperature and choline abnormalities in regions implicated in seizure onset and depression. Methods Twenty‐six patients with TLE and 26 controls completed questionnaires and underwent imaging at 3T. Volumetric echo‐planar MRSI/MRSI‐t data were processed within the Metabolite Imaging and Data Analysis System (MIDAS). Choline (CHO) was quantified as a ratio over creatine (CRE; CHO/CRE). Brain temperature (TCRE) was calculated based on the chemical shift difference of H2O relative to CRE's stable location on the ppm spectrum. The Hospital Anxiety and Depression Scale measured anxiety and depressive symptoms. The Chalfont Seizure Severity Scale measured seizure severity in patients with TLE. Two sets of voxelwise independent sample t tests examined group differences in CHO/CRE and TCRE maps. Voxel‐based multimodal canonical correlation analysis (mCCA) linked both datasets to investigate if, how, and where CHO/CRE and TCRE abnormalities were correlated in TLE participants and controls. Results Compared to controls, patients with TLE reported more depressive symptoms (P = 0.04) and showed CHO/CRE and TCRE elevations in left temporal and bilateral frontal regions implicated in seizure onset and depressive disorders (pFWE

Abstract This Opinion highlights several successful cases of biofuel technologies recently described by the IEA Bioenergy Intertask Report on Lessons Learned. The report discussed the potential of biofuels to contribute to a significant market supply, thus replacing fossil fuels and mitigating global warming, and it underscores the challenges in expanding biofuel production and replicating successful models between countries and regions. Based on the lessons learned from conventional, established technologies, the authors analyzed policies, feedstocks, products, technologies, economics, environmental concerns, social aspects, scalability, and ease of implementation and replication in different countries or regions. There are blending mandates in place around the world to foster the use of biofuels. Dependence on the availability and price fluctuations of crop feedstocks may limit biofuel production in certain circumstances. Legal restrictions on using food crops as feedstocks present obstacles to scaling up production. Temporary constraints related to feedstock costs and availability, as evidenced by changes and postponements of biofuel blending mandates in various countries (particularly during the COVID‐19 pandemic) also pose challenges. Technological hurdles exist for advanced biofuels that implicate premium pricing. Still, 2G ethanol from sugarcane meets very strict feedstock requirements with a carbon footprint so low that only electric vehicles charged in Norway could have life‐cycle GHG emissions at the same level as a 2G ethanol‐fueled combustion engine car. The authors evaluate whether and how much electrification could contribute to advance the decarbonization efforts in different countries. Drawing from these observations, the authors express their viewpoints to assist researchers and policymakers in the energy sector in formulating viable approaches to combat the climate crisis.

Abstract Introduction Despite various efforts to improve human papillomavirus (HPV) vaccine coverage in France, it has always been lower than in most other high‐income countries. The health authorities launched in 2018 the national PrevHPV research programme to (1) co‐develop with stakeholders and (2) evaluate the impact of a multicomponent complex intervention aimed at improving HPV vaccine coverage amongst French adolescents. Objective To describe the development process of the PrevHPV intervention using the GUIDance for rEporting of intervention Development framework as a guide. Methods To develop the intervention, we used findings from (1) published evidence on effective strategies to improve vaccination uptake and on theoretical frameworks of health behaviour change; (2) primary data on target populations' knowledge, beliefs, attitudes, preferences, behaviours and practices as well as the facilitators and barriers to HPV vaccination collected as part of the PrevHPV Programme and (3) the advice of working groups involving stakeholders in a participatory approach. We paid attention to developing an intervention that would maximise reach, adoption, implementation and maintenance in real‐world contexts. Results We co‐developed three components: (1) adolescents' and parents' education and motivation using eHealth tools (web conferences, videos, and a serious video game) and participatory learning at school; (2) general practitioners' e‐learning training on HPV using motivational interviewing techniques and provision of a decision aid tool and (3) easier access to vaccination through vaccination days organised on participating middle schools' premises to propose free of charge initiation of the HPV vaccination. Conclusion We co‐developed a multicomponent intervention that addresses a range of barriers and enablers of HPV vaccination. The next step is to build on the results of its evaluation to refine it before scaling it up if proven efficient. If so, it will add to the small number of multicomponent interventions aimed at improving HPV vaccination worldwide. Patient or Public Contribution The public (adolescents, their parents, school staff and health professionals) participated in the needs assessment using a mixed methods approach. The public was also involved in the components' development process to generate ideas about potential activities/tools, critically revise the successive versions of the tools and provide advice about the intervention practicalities, feasibility and maintenance.

Abstract Introduction Despite the Veterans Health Administration (VA) efforts to become a learning health system (LHS) and high‐reliability organization (HRO), interventions to build supportive learning environments within teams are not reliably implemented, contributing to high levels of burnout, turnover, and variation in care. Supportive learning environments build capabilities for teaching and learning, empower teams to safely trial and adapt new things, and adopt highly reliable work practices (eg, debriefs). Innovative approaches to create supportive learning environments are needed to advance LHS and HRO theory and research into practice. Methods To guide the identification of evidence‐based interventions that cultivate supportive learning environments, the authors used a longitudinal, mixed‐methods design and LHS and HRO frameworks. We partnered with the 81 VA cardiac catheterization laboratories and conducted surveys, interviews, and literature reviews that informed a Relational Playbook for Cardiology Teams. Results The Relational Playbook resources and 50 evidence‐based interventions are organized into five LHS and HRO‐guided chapters: Create a positive culture, teamwork, leading teams, joy in work, communication, and high reliability. The interventions are designed for managers to integrate into existing meetings or trainings to cultivate supportive learning environments. Conclusions LHS and HRO frameworks describe how organizations can continually learn and deliver nearly error‐free services. The Playbook resources and interventions translate LHS and HRO frameworks for real‐world implementation by healthcare managers. This work will cultivate supportive learning environments, employee well‐being, and Veteran safety while providing insights into LHS and HRO theory, research, and practice.

Abstract Introduction This systematic review sought predictors of unfavourable bleeding profiles in women using the etonogestrel contraceptive implant. Unfavourable bleeding is common and a leading cause of requests for removal. Methods We included randomised controlled trials (RCTs), and prospective and retrospective cohort studies from 1998 to October 2022. Inclusion criteria were healthy women using etonogestrel for contraception. Papers not in English were excluded as were ongoing or incomplete studies. We searched Pubmed, Pubmed Central, MEDLINE (Web of Science & Ovid), Cochrane library, CINAHL Plus, WHO (HINARI), Open Grey and Greynet.org. Risk of Bias was assessed using ROB2 IRPGv9 for RCTs and ROBINS‐I for non‐RCTs. We conducted a narrative analysis. Results We included 13 studies. Lower body mass index (BMI), younger age, parity and smoking status were statistically, significantly associated with unfavourable bleeding patterns in one or more studies. No studies reported post‐partum status having a significant association with unfavourable bleeding. The available data was too limited and too heterogeneous to perform a robust meta‐analysis. Discussion Heterogeneity in reported outcomes and timescales limited the accuracy of synthesis. Risk of bias was moderate to serious in non‐RCTs due to baseline differences and missing or imputed data. The protective effect of higher BMI for unfavourable bleeding is in keeping with previous reviews and studies and is a clinically important finding.

Abstract Date palm (Phoenix dactylifera L.) is able to grow and complete its life cycle while being rooted in highly saline soils. Which of the many well‐known salt‐tolerance strategies are combined to fine‐tune this remarkable resilience is unknown. The precise location, whether in the shoot or the root, where these strategies are employed remains uncertain, leaving us unaware of how the various known salt‐tolerance mechanisms are integrated to fine‐tune this remarkable resilience. To address this shortcoming, we exposed date palm to a salt stress dose equivalent to seawater for up to 4 weeks and applied integrative multi‐omics analyses followed by targeted metabolomics, hormone, and ion analyses. Integration of proteomic into transcriptomic data allowed a view beyond simple correlation, revealing a remarkably high degree of convergence between gene expression and protein abundance. This sheds a clear light on the acclimatization mechanisms employed, which depend on reprogramming of protein biosynthesis. For growth in highly saline habitats, date palm effectively combines various salt‐tolerance mechanisms found in both halophytes and glycophytes: “avoidance” by efficient sodium and chloride exclusion at the roots, and “acclimation” by osmotic adjustment, reactive oxygen species scavenging in leaves, and remodeling of the ribosome‐associated proteome in salt‐exposed root cells. Combined efficiently as in P. dactylifera L., these sets of mechanisms seem to explain the palm's excellent salt stress tolerance.

Background Recent randomized clinical trials have demonstrated that endovascular therapy for basilar artery occlusion is safe and potentially effective, predominantly in the non‐White population. The aim of this study was to identify predictors of good functional outcome in posterior circulation strokes in US population after mechanical thrombectomy from the TRACK (Trevo Stent‐Retriever Acute Stroke) and the NASA (North American Solitaire Stent Retriever Acute Stroke) registries from North America. Methods Patient‐level data from the TRACK and NASA registries were pooled, and patients with posterior circulation stroke were included in this analysis. Patients were dichotomized into those with 90‐day good functional outcome (modified Rankin scale [mRS] score 0–2) and poor functional outcome (mRS score ≥3). Baseline and procedural data were compared between the 2 cohorts. Multivariate logistic regression was performed to identify predictors of functional outcome. P

Abstract Objective Item response theory (IRT) is a methodological approach to studying the psychometric performance of outcome measures. This study aims to determine and summarize the use of IRT in otolaryngological scientific literature. Methods A systematic search of the Medline, Embase, and the Cochrane Library databases was performed for original English‐language published studies indexed up to January 28, 2023, per the following search strategy: (“item response theory” OR “irt” OR “rasch” OR “latent trait theory” OR “modern mental test theory”) AND (“ent” OR “otorhinolaryngology” OR “ear” OR “nose” OR “throat” OR “otology” OR “audiology” OR “rhinology” OR “laryngology” OR “neurotology” OR “facial plastic surgery”). Results Fifty‐five studies were included in this review. IRT was used across all subspecialties in otolaryngology, and most studies utilizing IRT methodology were published within the last decade. Most studies analyzed polytomous response data, and the most commonly used IRT models were the partial credit and the rating scale model. There was considerable heterogeneity in reporting the main assumptions and results of IRT. Conclusion IRT is increasingly being used in the otolaryngological scientific literature. In the otolaryngology literature, IRT is most frequently used in the study of patient‐reported outcome measures and many different IRT‐based methods have been used. Future IRT‐based outcome studies, using standardized reporting guidelines, might improve otolaryngology‐outcome research sustainably by improving response rates and reducing patient response burden. Level of evidence 2.

Abstract Aim Nurse‐led care aims to optimize the discharge preparation with a focus on increasing patients' independency and self‐care abilities. This study compared patients' improvements of self‐care abilities and frequency of readmission rate between nurse‐led care and regular nursing care within the acute hospital setting. Design A quasi‐experimental design within a real‐world setting was used for this work. Methods We included a pool of 2501 patients from a control group (medically stable in usual care) and 420 patients from an intervention group (nurse‐led care). After propensity score matching, the study cohort consisted of 612 patients. Results From admission to discharge, nurse‐led care patients showed superior improvements of total self‐care abilities compared to usual care patients. In particular, we found improvements in the following categories: mobility, grooming and excretion. Patients with nurse‐led care were furthermore less frequently readmitted to hospital compared with the control group patients. Patient or public contribution No patient or public contribution.

Abstract Cave carbonates, seemingly growing in defiance of gravity, have attracted the community's interest for more than a century. This paper focusses on ‘helictites’, contorted vermiform speleothems with central capillaries. Petrographic, crystallographic and geochemical data of calcitic and aragonitic helictites (recent to 347 ka) from three caves in Western Germany are placed in context with previous work. Aragonitic helictites from one site, the Windloch Cave, form exceptionally large and complex structures that share similarities with the celebrated helictite arrays in the Asperge Cave in France. Aragonitic and calcitic helictites differ significantly in their crystal fabrics and internal geometry. Calcitic helictites are best described as a composite crystal fabric consisting of fibrous mesocrystals. Aragonite helictites display a complex fabric of acicular to platy crystals, some of which show evidence for growth‐twinning and perhaps crystallisation via a monoclinal precursor stage. The micro‐tomographic characterisation of several orders of channels and their complex architecture raises important questions regarding fluid migration and helictite architecture. In terms of their isotope geochemistry, helictites are depleted in 13C to various degrees, isotope values that are controlled by the mixing of fluids and mineralogy‐related fractionation. Regarding their δ18O values, most helictites overlap with other calcitic and aragonitic speleothems. Previous models explaining the twisted morphology of helictites are discussed from the viewpoint of fluid migration and CO2 degassing rates, mineralogy and helictite petrography. For the complex aragonitic helicities documented here, the most likely mechanisms to explain the contorted growth forms include the internal capillary network combined with localised (sector) growth at the helictite tip. The morphologically simpler calcitic helictites are best explained by capillary and surface flow. Future work should include geomicrobiology to assess the significance of induced mineralisation and transmission electron microscopy analysis to more quantitatively assign crystallographic properties.

Abstract Gonorrhea is a sexually transmitted infection for which antibiotic treatment options have declined due to increasing antibiotic resistance. Zoliflodacin, an investigational oral spiropyrimidinetrione antibiotic with activity against Neisseria gonorrhoeae strains that are multidrug‐resistant, including to third‐generation cephalosporins, is in phase III development for uncomplicated gonorrhea. This phase I, parallel, open‐label, randomized, crossover study in healthy adults evaluated the effect of food on the pharmacokinetics of single 3 or 4 g doses of zoliflodacin administered as granules for oral suspension in the fasted state or after consumption of a standardized high‐fat meal. Forty‐seven out of 48 randomized subjects completed the study. Oral administration of zoliflodacin with food delayed the absorption rate, compared with fasted state, with time to maximum concentration (Tmax) increasing from 3 to 6 h for the 3 g dose, and 2.5 to 4 h for the 4 g dose, but had no impact on the elimination of zoliflodacin. The maximum concentration (Cmax) and area under the plasma concentration‐time curve from time 0 to 24 h (AUC(0–24)) significantly increased with food by 52% and 94% for the 3 g dose, and by 89% and 108% for the 4 g dose. Forty‐two percent of participants reported a total of 34 treatment‐emergent adverse events (TEAEs), which were all considered mild in severity. Headache was the most common TEAE (22/48 subjects, 45.8%) and the only TEAE reported in more than one subject. In conclusion, administration of single 3 and 4 g doses of zoliflodacin as granules for oral suspension, with a high‐fat meal was well‐tolerated and resulted in statistically significant increases in peak and overall systemic exposure to zoliflodacin.

Abstract We propose a novel method to assess delayed primacy in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as an outcome; demographic, clinical, and apolipoprotein E (APOE) data as covariates; and cognitive predictors, including delayed primacy. Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. Sex differential associations were observed. We conclude that CERAD‐derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals. Highlights We propose a novel method to analyse serial position in the CERAD memory test. We analyse data from 1096 individuals who were cognitively unimpaired at baseline. Delayed primacy predicts post mortem pathology better than traditional metrics.

Abstract INTRODUCTION Hearing loss is highly prevalent among older adults and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a multicenter randomized control trial (partially nested within the infrastructure of an observational cohort study, the Atherosclerosis Risk in Communities [ARIC] study) to determine the efficacy of best‐practice hearing treatment to reduce cognitive decline over 3 years. The goal of this paper is to describe the recruitment process and baseline results. METHODS Multiple strategies were used to recruit community‐dwelling 70–84‐year‐old participants with adult‐onset hearing loss who were free of substantial cognitive impairment from the parent ARIC study and de novo from the surrounding communities into the trial. Participants completed telephone screening, an in‐person hearing, vision, and cognitive screening, and a comprehensive hearing assessment to determine eligibility. RESULTS Over a 24‐month period, 3004 telephone screenings resulted in 2344 in‐person hearing, vision, and cognition screenings and 1294 comprehensive hearing screenings. Among 1102 eligible, 977 were randomized into the trial (median age = 76.4 years; 53.5% female; 87.8% White; 53.3% held a Bachelor's degree or higher). Participants recruited through the ARIC study were recruited much earlier and were less likely to report hearing loss interfered with their quality of life relative to participants recruited de novo from the community. Minor differences in baseline hearing or health characteristics were found by recruitment route (i.e., ARIC study or de novo) and by study site. DISCUSSION The ACHIEVE study successfully completed enrollment over 2 years that met originally projected rates of recruitment. Substantial operational and scientific efficiencies during study startup were achieved through embedding this trial within the infrastructure of a longstanding and well‐established observational study. Highlights The ACHIEVE study tests the effect of hearing intervention on cognitive decline. The study is partially nested within an existing cohort study. Over 2 years, 977 participants recruited and enrolled. Eligibility assessed by telephone and in‐person for hearing, vision, and cognitive screening. The ACHIEVE study findings will have significant public health implications.

Abstract Background TP53 mutation is present in about 50.8% of lung adenocarcinomas, frequently in combination with other genetic alterations. However, a rare subset harbors the TP53 mutation alone. Methods Next‐generation sequencing was performed in 844 lung adenocarcinomas diagnosed by fine needle aspiration. Fourteen cases (1.7%) showed isolated TP53 alteration and were subjected to a comprehensive analysis. Results The average age at diagnosis was 65.7 years (range 48–79); 9 males and 5 females. All were smokers with an average pack‐year of 40.7 (range 10–70). Ten had metastases, mostly in the brain (n = 4) and pleura (n = 4). After a follow‐up period of up to 102 months, 9 died, 3 were alive free of disease, 1 was alive with disease, and 1 was lost to follow‐up. The median survival was 12.2 months. Most tumors exhibited poor differentiation, composed of solid sheets with moderate to severe atypia, increased mitotic activity, and necrotic background. Half were positive for TTF‐1 and showed p53 overexpression. PD‐L1 was positive in 5 cases. Most alterations were missense mutations in exons 5–8, and this mutation type was associated with p53 overexpression. Tumors with combined missense mutation and truncated protein had higher PD‐L1 expression along with a trend towards an increase in tumor mutational burden (TMB). CEBPA deletion of undetermined significance was the most common copy number alteration. Conclusion Isolated TP53 mutation was seen in association with smoking, high‐grade cytomorphologic features, adverse prognosis, and recurrent CEBPA deletions. These tumors tend to have strong PD‐L1 expression and high TMB, suggesting potential benefit from immune checkpoint inhibitors. Hence, the recognition of this molecular group has prognostic and therapeutic implications.

Abstract Background The significance of different histological spreading patterns of tumor tissue in oral tongue squamous cell carcinoma (TSCC) is well known. Our aim was to construct a numeric parameter on a continuous scale, that is, the modified Polsby–Popper (MPP) score, to describe the aggressiveness of tumor growth and infiltration, with the potential to analyze hematoxylin and eosin‐stained whole slide images (WSIs) in an automated manner. We investigated the application of the MPP score in predicting survival and cervical lymph node metastases as well as in determining patients at risk in the context of different surgical margin scenarios. Methods We developed a semiautomated image analysis pipeline to detect areas belonging to the tumor tissue compartment. Perimeter and area measurements of all detected tissue regions were derived, and a specific mathematical formula was applied to reflect the perimeter/area ratio in a comparable, observer‐independent manner across digitized WSIs. We demonstrated the plausibility of the MPP score by correlating it with well‐established clinicopathologic parameters. We then performed survival analysis to assess the relevance of the MPP score, with an emphasis on different surgical margin scenarios. Machine learning models were developed to assess the relevance of the MPP score in predicting survival and occult cervical nodal metastases. Results The MPP score was associated with unfavorable tumor growth and infiltration patterns, the presence of lymph node metastases, the extracapsular spread of tumor cells, and higher tumor thickness. Higher MPP scores were associated with worse overall survival (OS) and tongue carcinoma‐specific survival (TCSS), both when assessing all pT‐categories and pT1‐pT2 categories only; moreover, higher MPP scores were associated with a significantly worse TCSS in cases where a cancer‐free surgical margin of

Abstract Insect pests cause significant damage to food production, so early detection and efficient mitigation strategies are crucial. There is a continual shift toward machine learning (ML)‐based approaches for automating agricultural pest detection. Although supervised learning has achieved remarkable progress in this regard, it is impeded by the need for significant expert involvement in labeling the data used for model training. This makes real‐world applications tedious and oftentimes infeasible. Recently, self‐supervised learning (SSL) approaches have provided a viable alternative to training ML models with minimal annotations. Here, we present an SSL approach to classify 22 insect pests. The framework was assessed on raw and segmented field‐captured images using three different SSL methods, Nearest Neighbor Contrastive Learning of Visual Representations (NNCLR), Bootstrap Your Own Latent, and Barlow Twins. SSL pre‐training was done on ResNet‐18 and ResNet‐50 models using all three SSL methods on the original RGB images and foreground segmented images. The performance of SSL pre‐training methods was evaluated using linear probing of SSL representations and end‐to‐end fine‐tuning approaches. The SSL‐pre‐trained convolutional neural network models were able to perform annotation‐efficient classification. NNCLR was the best performing SSL method for both linear and full model fine‐tuning. With just 5% annotated images, transfer learning with ImageNet initialization obtained 74% accuracy, whereas NNCLR achieved an improved classification accuracy of 79% for end‐to‐end fine‐tuning. Models created using SSL pre‐training consistently performed better, especially under very low annotation, and were robust to object class imbalances. These approaches help overcome annotation bottlenecks and are resource efficient.

The United States witnessed a nearly 4‐fold increase in personal health care expenditures between 1980 and 2010. Despite innovations and obvious benefits to health, participants enrolled in clinical trials still do not accurately represent the racial and ethnic composition of patients nationally or globally. This lack of diversity in cohorts limits the generalizability and significance of results among all populations and has deep repercussions for patient equity. To advance diversity in clinical trials, robust evidence for the most effective strategies for recruitment of diverse participants is needed. A major limitation of previous literature on clinical trial diversity is the lack of control or comparator groups for different strategies. To date, interventions have focused primarily on (1) community‐based interventions, (2) institutional practices, and (3) digital health systems. This review article outlines prior intervention strategies across these 3 categories and considers health policy and ethical incentives for substantiation before US Food and Drug Administration approval. There are no current studies that comprehensively compare these interventions against one another. The American Heart Association Strategically Focused Research Network on the Science of Diversity in Clinical Trials represents a multicenter, collaborative network between Stanford School of Medicine and Morehouse School of Medicine created to understand the barriers to diversity in clinical trials by contemporaneous head‐to‐head interventional strategies accessing digital, institutional, and community‐based recruitment strategies to produce informed recruitment strategies targeted to improve underrepresented patient representation in clinical trials.

Abstract Objective This study was performed to identify coexisting structural lesions in patients with epilepsy and known temporal encephaloceles (TEs). Methods Forty‐seven structural magnetic resonance imaging (MRI) scans of patients with epilepsy and radiologically diagnosed TEs were retrospectively reviewed visually and using an automated postprocessing software, the Morphometric Analysis Program v2018 (MAP18), to depict additional subtle, potentially epileptogenic lesions in the 3D T1‐weighted MRI data. All imaging findings were evaluated in the context of clinical and electroencephalographical findings. Results The study population consisted of 47 epilepsy patients (38.3% female, n = 18). The median age at the time of the scan was 40 years (range 12–81 years). Twenty‐one out of 47 MRI scans (44.7%) showed coexisting lesions in the initial MRI evaluation; in 38.3% (n = 18) of patients, those lesions were considered probably epileptogenic. After postprocessing, probable epileptogenic lesions were identified in 53.2% (n = 25) of patients. Malformations of cortical development had initially been reported in 17.0% (n = 8) of patients with TEs, which increased to 38.3% (n = 18) after postprocessing. TEs and other epileptogenic lesions were considered equally epileptogenic in 21.3% (n = 10) of the cases in the initial MR reports and 25.5% (n = 12) of the cases after postprocessing. Significance Temporal encephaloceles are a potential cause of MRI‐negative temporal lobe epilepsy. According to our data, TEs can occur with other lesions, suggesting that increased awareness is also required in patients with lesional epilepsy. TEs may not always be epileptogenic; hence, their occurrence with other structural pathologies may influence the presurgical evaluation and surgical approach. Finally, TEs can be associated with malformations of cortical development, which may indicate a common developmental etiology of those lesions.

Abstract Aims Sinus tachycardia potentially leads to a deterioration of cardiac function in critically ill infants. The ultrashort‐acting beta‐blocker landiolol hydrochloride is a new pharmacological option for a selective heart rate (HR) control in patients with sinus tachycardia and heart failure. Methods and results This study was a monocentric retrospective medical chart review study at the University Children's Hospital Bonn (Germany) from 01 January 2018 until 30 June 2020. This study included a cohort of 62 term and preterm infants with a diagnosis of ventricular dysfunction and/or pulmonary hypertension (PH), in combination with preexisting tachycardia and treatment with landiolol hydrochloride. Infants were allocated to subgroups according to weeks of gestational age (GA): born at 35 weeks of GA (Group B). Tachycardia was defined depending on GA (170 b.p.m.; ≥ 35 weeks of GA: >150 b.p.m.). The primary endpoint was defined as percentage of patients achieving HR normalization during the first 24 h of landiolol treatment. Twenty‐nine infants were allocated to Group A and 33 infants to Group B. The overall median GA of the infants was 35.3 (23.3/41.3), with 53% female infants. The primary endpoint was achieved in 57 patients (91.9%). The median time to reach target HR was 1.8 (0.3–24) h. The median starting dose of landiolol was 8.8 (3.9–25.3) μk/kg/min, with a median dosing during the first 24 h of landiolol treatment of 9.9 (2.8–35.4) μk/kg/min. The median landiolol dose while achieving the target HR was 10 (2.4–44.4) μk/kg/min. The right ventricular dysfunction improved significantly in both groups 24 h after onset of landiolol infusion (P = 0.001 in Group A and P = 0.045 in Group B). The left ventricular and biventricular dysfunction improved significantly 24 h after onset of landiolol infusion in infants of Group B (P = 0.004 and P = 0.006, respectively). The severity of PH improved significantly after 24 h in infants of Group A (P

Abstract Aims Kidney function changes dynamically during AHF treatment, but risk factors for and consequences of worsening renal function (WRF) at hospital admission are uncertain. We aimed to determine the significance of WRF at admission for acute heart failure (AHF). Methods and results We evaluated a subgroup of 406 patients from The Acute Kidney Injury Neutrophil gelatinase–associated lipocalin Evaluation of Symptomatic heart failure Study (AKINESIS) who had serum creatinine measurements available within 3 months before and at the time of admission. Admission WRF was primarily defined as a 0.3 mg/dL or 50% creatinine increase from preadmission. Alternative definitions evaluated were a ≥0.5 mg/dL creatinine increase, ≥25% glomerular filtration rate decrease, and an overall change in creatinine. Predictors of admission WRF were evaluated. Outcomes evaluated were length of hospitalization, a composite of adverse in‐hospital events, and the composite of death or HF readmission at 30, 90, and 365 days. Biomarkers' prognostic ability for these outcomes were evaluated in patients with admission WRF. One‐hundred six patients (26%) had admission WRF. These patients had features of more severe AHF with lower blood pressure, higher BUN, and lower serum sodium concentrations at admission. Higher BNP (odds ratio [OR] per doubling 1.16–1.28, 95% confidence interval [CI] 1.00–1.55) and lower diastolic blood pressure (OR 0.97–0.98, 95% CI 0.96–0.99) were associated with a higher odds for the three definitions of admission WRF. The primary WRF definition was not associated with a longer hospitalization, but alternative WRF definitions were (1.3 to 1.6 days longer, 95% CI 1.0–2.2). WRF across definitions was not associated with a higher odds of adverse in‐hospital events or a higher risk of death or HF readmission. In the subset of patients with WRF, biomarkers were not prognostic for any outcome. Conclusions Admission WRF is common in AHF patients and is associated with an increased length of hospitalization, but not adverse in‐hospital events, death, or HF readmission. Among those with admission WRF, biomarkers did not risk stratify for adverse events.

Abstract Aims Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart‐healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16 kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)‐146a‐dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. Methods and results Postpartum (PP) female PPCM‐prone mice with a cardiomyocyte restricted STAT3‐deficiency (αMHC‐Cretg/+; Stat3fl/fl; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5 mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum‐matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5 ± 9.4% vs. CKO: 22.1 ± 9%, P

Abstract Inherited metabolic disorders (IMDs) comprise a heterogeneous class of genetic disorders characterized by impaired biochemical functions in metabolism. However, incidences and outcomes of patients hospitalized with IMDs are largely unknown. We conducted a population‐based cohort study using nationwide in‐hospital claims data in Switzerland from 2012 to 2020. We assessed incidence rates of hospitalizations and hospital‐associated outcomes, stratified in five age groups (0–9, 10–19, 20–39, 40–59, and 60–90 years) and three types of IMDs (peptide, amine and amino acid metabolism disorders [AD], carbohydrate metabolism disorders [CD], fatty acid, and ketone body metabolism disorders [FD]). A total of 7293 hospitalizations with IMD were identified, of which 3638 had AD, 3153 CD, and 502 FD. Incidence rates for hospitalizations per 100 000 person‐years were highest under the age of 10 years across all types of IMDs (8.69 for AD, 5.73 for CD, 3.71 for FD) and decreased thereafter. In patients with AD and CD, hospitalization rates increased again in adults aged 60–90 years (7.28 for AD, 7.25 for CD), while they remained low in patients with FD (0.31). Compared to inpatients without IMD, adult IMD patients had a higher burden of hospital‐associated adverse outcomes including an increased risk of in‐hospital mortality, intensive care unit admission, mechanical ventilation, and longer length of hospital or intensive care unit stay. Incremental risk of 30‐day, 1‐year, and 2‐year hospital readmission was highest among children and adolescents with IMD.

Abstract Super‐resolution optical imaging tools are crucial in microbiology to understand the complex structures and behavior of microorganisms such as bacteria, fungi, and viruses. However, the capabilities of these tools, particularly when it comes to imaging pathogens and infected tissues, remain limited. MicroMagnify (µMagnify) is developed, a nanoscale multiplexed imaging method for pathogens and infected tissues that are derived from an expansion microscopy technique with a universal biomolecular anchor. The combination of heat denaturation and enzyme cocktails essential is found for robust cell wall digestion and expansion of microbial cells and infected tissues without distortion. µMagnify efficiently retains biomolecules suitable for high‐plex fluorescence imaging with nanoscale precision. It demonstrates up to eightfold expansion with µMagnify on a broad range of pathogen‐containing specimens, including bacterial and fungal biofilms, infected culture cells, fungus‐infected mouse tone, and formalin‐fixed paraffin‐embedded human cornea infected by various pathogens. Additionally, an associated virtual reality tool is developed to facilitate the visualization and navigation of complex 3D images generated by this method in an immersive environment allowing collaborative exploration among researchers worldwide. µMagnify is a valuable imaging platform for studying how microbes interact with their host systems and enables the development of new diagnosis strategies against infectious diseases.