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Abstract Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real‐world data. For lactation‐focused PBPK (Lact‐PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact‐PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast‐fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non‐invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact‐PBPK models.

Abstract Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose–response relationships are not yet fully understood. Therefore, the objective of this model‐based meta‐analysis (MBMA) was to establish dose–response for COCs containing different progestin/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3 months at the highest (30 μg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20 μg), irrespective of the progestin used. The dose–response relationships established for BTB across different progestin/EE combinations can now be used to support the selection of optimal COC dosing/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug–drug interactions and demographics, on BTB.

Abstract Breastfeeding is important in childhood development, and medications are often necessary for lactating individuals, yet information on the potential risk of infant drug exposure through human milk is limited. Establishing a lactation modeling framework can advance our understanding of this topic and potentiate clinical decision making. We expanded the modeling framework previously developed for sotalol using pregabalin as a second prototypical probe compound with similar absorption, distribution, metabolism, and elimination (ADME) properties. Adult oral models were developed in PK‐Sim® and used to build a lactation model in MoBi® to simulate drug transfer into human milk. The adult model was applied to breastfeeding pediatrics (ages 1 to 23 months) and subsequently integrated with the lactation model to simulate infant drug exposure according to age, size, and breastfeeding frequency. Physiologically based pharmacokinetic (PBPK) model simulations captured the data used for verification both in adults and pediatrics. Lactation simulations captured observed milk and plasma data corresponding to doses of 150 mg administered twice daily to lactating individuals, and estimated a relative infant dose (RID) of approximately 7% of the maternal dose. The infant drug exposure simulations showed peak plasma concentrations of 0.44 μg/mL occurring within the first 2 weeks of life, followed by gradual decline with age after week four. The modeling framework performs well for this second prototypical drug and warrants expansion to other drugs for further validation. PBPK modeling and simulation approaches together with clinical lactation data could ultimately help inform infant drug exposure risk assessments to guide clinical decision making.

Abstract Effective approaches are needed to conserve the planet's remaining wildlife and wilderness landscapes, especially concerning global biodiversity conservation targets. Here, we present a new software system called EarthRanger: an open‐source platform built to help monitor, research and manage ecosystems. EarthRanger consists of seven main components (Core Server, API, Storage, Gundi, Web App, Mobile App, Ecoscope) that provide functionality for data (i) aggregation & collection, (ii) storage & management, (iii) real‐time and post hoc analysis, (iv) visualisation and (v) dissemination. The mobile application provides field‐based data recording and visualisation tools. EarthRanger may be deployed for single project use or can aggregate across multiple geographies as a centralised hub. EarthRanger can be used to collect standardised tracking data (e.g. from wildlife collars, vehicles and ranger patrols) and configurable event information (e.g. a singular recording with associated user‐defined attribute information such as a wildlife sighting or encounter with a poacher). Since development began in 2015, the platform has (at the time of writing) been deployed at over 500 sites across 70 countries and with myriad configurations and objectives. EarthRanger has improved the ability to monitor data feeds and manage conservation‐related operations in real time. For instance, the deployment of EarthRanger by African Parks has led to the removal of over 50,000 snares, steady population growth of key species of concern and near cessation of poaching. In Liwonde's protected area, enhanced mitigation efforts supported by EarthRanger reduced the number of deaths from wildlife conflict by more than 91%. EarthRanger is also providing a platform to enhance standardisation, aggregation, transfer and long‐term storage of ecological information and promote collaboration between groups conducting protected area management and ecology and biodiversity research.

Abstract Sickle cell disease is a rare genetic disease resulting from an abnormality in hemoglobin. Hemostasis in the steady state, defined as ≥2 months without vaso‐occlusive crises, is poorly described in the literature. We report the routine hemostasis profile in steady state patients with sickle cell disease (SCD), including during pregnancy and according to phenotype. This retrospective study collected data over the period 2010 to 2021. Data on routine hemostasis parameters (prothrombin time [PT] activated partial thromboplastin time [aPTT], and platelets) were collected from medical records and were compared with laboratory norms including during pregnancy; the HbSS phenotype was compared with the HbSC, HbSB°thalassemia, and HbSB+thalassemia phenotypes. we included 119 adults (representing 190 day‐hospitals) with SCD who had attended at least one checkup in the steady state. Seven patients (15 day‐hospitals) on anticoagulants were excluded. Eleven (17 day‐hospitals) were pregnant. Mean routine hemostasis parameters were within normal values regardless of pregnancy. Mean PT was lower during pregnancy (12.3 ± 0.6 s vs. 13.2 ± 1.0 s; P = .01). PT and platelet counts were higher (P = .01) and aPTT was lower (P = .03) in men and nonpregnant women in the HbSS group compared with those in the HbSC group. routinely collected hemostasis parameters in steady state patients were within normal laboratory values, including in pregnant women. PT values differed significantly between pregnant women and nonpregnant women, and PT, aPTT, and platelet counts differed between HbSS, HbSC, and HbSB+thalassemia phenotypes.

Abstract Conventional active SONAR systems often use beamformers and matched filters separately to extract bearing and range information from the received signal and offer a straightforward way of creating a two‐dimensional map of the environment. In SONAR systems the minimum‐variance‐distortionless‐response beamformer (MVDR beamformer) is a commonly used type of beamformer, which will reconstruct the receive signal from a certain direction optimally. In terms of detecting the transmit signal, the most used method is the conventional matched filter. Both algorithms are simple to implement and perform well under various noise scenarios. The proposed method combines the beamformer and matched filter by introducing an extended channel model that allows the derivation of a multichannel Wiener filter to solve for the unknown reflection coefficients of the complete two‐dimensional environment. This results in adaptively calculated filter weights that will drastically improve the performance compared to a separate MVDR beamformer and matched filter. In addition, a parameter is introduced with which one can arbitrarily adjust the focus between angular and temporal resolution depending on the application. After the derivation, the performance is demonstrated with simulations and measurements.

Abstract Background Brain imaging suggests the involvement of the limbic system, particularly the cingulate gyrus (GC), in dogs with idiopathic epilepsy (IE). Hypothesis A correlation exists between the side of interictal epileptiform discharges (IEDs) and the volume of the ipsilateral GC (GCe) in dogs with IE. Animals Dogs admitted to the neurological consultation (32 with epileptic seizures and 13 control) were included. Methods This retrospective, blinded study followed the International Veterinary Epilepsy Task Force recommendations for diagnosing IE at the Tier III confidence level. The IE group included 18 and 14 dogs with IEDs in the left and right hemispheres, respectively (median age: 36 months, median weight: 19.5 kg), whereas the control group included 13 dogs (median age: 32 months, median weight: 20 kg). Whole‐brain and GC‐volumetric assessments were performed by a semiautomated method. Results In the control group, the volume of the GC was: left, from 743.63 to 1001.61 mm3, right, from 789.35 to 1015.86 mm3. In the study group, the volume of the GC was: left, from 720.88 to 1054.9 mm3 and right, from 566.29 to 987.77 mm3. In dogs with IE, GCe volume was significantly lower than the mean volume of the GC in the control group relative to total intracranial volume (TIV; P = .00044). Conclusions and Clinical Importance Alterations in the volume of the GC provide insights into structural changes during IE. The use of semiautomatic volumetry provides an advantage by reducing the potential for human error.

Abstract Clinical trials seeking to delay or prevent the onset of type 1 diabetes (T1D) face a series of pragmatic challenges. Despite more than 100 years since the discovery of insulin, teplizumab remains the only FDA‐approved therapy to delay progression from Stage 2 to Stage 3 T1D. To increase the efficiency of clinical trials seeking this goal, our project sought to inform T1D clinical trial designs by developing a disease progression model‐based clinical trial simulation tool. Using individual‐level data collected from the TrialNet Pathway to Prevention and The Environmental Determinants of Diabetes in the Young natural history studies, we previously developed a quantitative joint model to predict the time to T1D onset. We then applied trial‐specific inclusion/exclusion criteria, sample sizes in treatment and placebo arms, trial duration, assessment interval, and dropout rate. We implemented a function for presumed drug effects. To increase the size of the population pool, we generated virtual populations using multivariate normal distribution and ctree machine learning algorithms. As an output, power was calculated, which summarizes the probability of success, showing a statistically significant difference in the time distribution until the T1D diagnosis between the two arms. Using this tool, power curves can also be generated through iterations. The web‐based tool is publicly available: https://app.cop.ufl.edu/t1d/. Herein, we briefly describe the tool and provide instructions for simulating a planned clinical trial with two case studies. This tool will allow for improved clinical trial designs and accelerate efforts seeking to prevent or delay the onset of T1D.

Abstract Background Laser balloon (LB) pulmonary vein isolation (PVI) is an established ablation technique for atrial fibrillation (AF). We report long‐term follow‐up and procedural data of LB‐PVI and we compare the first and second LB generation. Methods Patients undergoing LB ablation with first‐ (LB1) or second‐generation LB (LB2) for AF were retrospectively enrolled and divided into two groups. Procedural endpoint was complete PVI. Clinical success was defined as no recurrence of AF/atrial tachycardia after a 90 days blanking period. Results 538 patients were included (age 66 ± 10 years, 58% paroxysmal AF), 427 in LB1 and 111 in LB2. 2079 PVs were targeted and 2073 (99.7%) were successfully isolated; 2027 (97.5%) using solely the LB. Additional touch‐up ablation was limited (46 PVs; 2.2%) with no difference between the groups. Procedural (LB1: 120 ± 33 minutes vs. LB2: 99 ± 22 min; p

Abstract Aims Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) with profound left ventricular (LV) failure is associated with inadequate LV emptying. To unload the LV, VA‐ECMO can be combined with Impella CP (ECMELLA). We hypothesized that ECMELLA improves cardiac energetics compared with VA‐ECMO in a porcine model of cardiogenic shock (CS). Methods and results Land‐race pigs (weight 70 kg) were instrumented, including a LV conductance catheter and a carotid artery Doppler flow probe. CS was induced with embolization in the left main coronary artery. CS was defined as reduction of ≥50% in cardiac output or mixed oxygen saturation (SvO2) or a SvO2

Abstract Objective Krabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late‐onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late‐onset KD (LOKD). Methods Additionally to cerebral MRI, protein structural analyses of the β‐galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β‐glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts. Results Exome sequencing revealed biallelic likely pathogenic variants: GALC exons 11–17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected. Interpretation The presented LOKD case underlines the age‐dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.

Abstract The capability to observe temporal changes on Io's surface at optical wavelengths has recently been demonstrated by Conrad et al. (2024, https://doi.org/10.1029/2024GL108609) using new instrumentation at the Large Binocular Telescope. Monitoring of Io's surface morphology would be impactful since preexisting metrics of the degree, location and composition of Io's plume activities are severely limited. Relationships with external data sets appear especially fruitful. Comparisons with spatially resolved data on gas distributions and thermal hots spots would better characterize composition and chemistry in Io's volcanic plumes. Comparisons with measurements remote from Io are posed to advance our understanding of atmospheric escape and how eruptions connect to transient enhancements at disparate size and time scales in the extended neutral clouds and plasma torus.

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 Biochar is the product of intentional pyrolysis of organic feedstocks. It is made under controlled conditions in order to achieve desired physico‐chemical characteristics. These characteristics ultimately affect biochar properties as a soil amendment. When biochar is used for carbon storage, an important property is its persistence in soil, often described by the proportion of biochar carbon remaining in soil after a 100 years (Fperm). We analyzed published data on 1230 biochars to re‐evaluate the effect of pyrolysis parameters on biochar characteristics and the possibility to predict Fperm from the maximum temperature reached during pyrolysis (HTT). We showed that biochar ash and nitrogen (N) contents were mostly affected by feedstock type. The oxygen to carbon (O:C) and hydrogen to carbon (H:C) ratios were mostly affected by the extent of pyrolysis (a combination of HTT and pyrolysis duration), except for non (ligno)cellulosic feedstocks (plastic waste, sewage sludge). The volatile matter (VM) content was affected by both feedstock type and the extent of pyrolysis. We demonstrated that HTT is the main driver of H:C ‐‐ an indicator of persistence ‐‐ but that it is not measured accurately enough to precisely predict H:C, let alone persistence. We examined the equations to estimate Fperm available in the literature and showed that Fperm calculated from HTT presented little agreement with Fperm calculated from H:C. The sign and magnitude of the bias depended on the equation used to calculate Fperm and the dispersion was usually large. This could lead to improper compensation of carbon emissions and wrong reporting of carbon sinks in national carbon accounting schemes. We recommend not to use HTT as a predictor for persistence and stress the importance to rapidly develop more accurate proxies of biochar C persistence in soil.

ABSTRACT Anaerobic digestion and composting of biowastes are vital pathways to recycle carbon and nutrients for agriculture. However, plastic contamination of soil amendments and fertilizers made from biowastes is a relevant source of (micro‐) plastics in (agricultural) ecosystems. To avoid this contamination, plastic containing biowastes could be pyrolyzed to eliminate the plastic, recycle most of the nutrients, and create carbon sinks when the resulting biochar is applied to soil. Literature suggests plastic elimination mainly by devolatilization at co‐pyrolysis temperatures of > 520°C. However, it is uncertain if the presence of plastic during biomass pyrolysis induces the formation of organic contaminants or has any other adverse effects on biochar properties. Here, we produced biochar from wood residues (WR) obtained from sieving of biowaste derived digestate. The plastic content was artificially enriched to 10%, and this mixture was pyrolyzed at 450°C and 600°C. Beech wood (BW) chips and the purified, that is, (macro‐) plastic‐free WR served as controls. All biochars produced were below limit values of the European Biochar Certificate (EBC) regarding trace element content and organic contaminants. Under study conditions, pyrolysis of biowaste, even when contaminated with plastic, can produce a biochar suitable for agricultural use. However, thermogravimetric and nuclear magnetic resonance spectroscopic analysis of the WR + 10% plastics biochar suggested the presence of plastic residues at pyrolysis temperatures of 450°C. More research is needed to define minimum requirements for the pyrolysis of plastic containing biowaste and to cope with the automated identification and determination of plastic types in biowaste at large scales.

ABSTRACT Biocides are used to control microorganisms across different applications, but emerging resistance may pose risks for those applications. Resistance to biocides has commonly been studied using adaptive laboratory evolution (ALE) experiments with growth at subinhibitory concentrations linked to serial subculturing. It has been shown recently that Escherichia coli adapts to repeated lethal stress imposed by the biocide benzalkonium chloride (BAC) by increased survival (i.e., tolerance) and not by evolving the ability to grow at increased concentrations (i.e., resistance). Here, we investigate the contributions of evolution for tolerance as opposed to resistance for the outcome of ALE experiments with E. coli exposed to BAC. We find that BAC concentrations close to the half maximal effective concentration (EC50, 4.36 μg mL−1) show initial killing (~40%) before the population resumes growth. This indicates that cells face a two‐fold selection pressure: for increased survival and for increased growth. To disentangle the effects of both selection pressures, we conducted two ALE experiments: (i) one with initial killing and continued stress close to the EC50 during growth and (ii) another with initial killing and no stress during growth. Phenotypic characterization of adapted populations showed that growth at higher BAC concentrations was only selected for when BAC was present during growth. Whole genome sequencing revealed distinct differences in mutated genes across treatments. Treatments selecting for survival‐only led to mutations in genes for metabolic regulation (cyaA) and cellular structure (flagella fliJ), while treatments selecting for growth and survival led to mutations in genes related to stress response (hslO and tufA). Our results demonstrate that serial subculture ALE experiments with an antimicrobial at subinhibitory concentrations can select for increased growth and survival. This finding has implications for the design of ALE experiments to assess resistance risks of antimicrobials in different scenarios such as disinfection, preservation, and environmental pollution.

Abstract Escherichia coli A0 34/86 (EcO83) is a probiotic strain used in newborns to prevent nosocomial infections and diarrhoea. This bacterium stimulates both pro‐ and anti‐inflammatory cytokine production and its intranasal administration reduces allergic airway inflammation in mice. Despite its benefits, there are concerns about the use of live probiotic bacteria due to potential systemic infections and gene transfer. Extracellular vesicles (EVs) derived from EcO83 (EcO83‐EVs) might offer a safer alternative to live bacteria. This study characterizes EcO83‐EVs and investigates their interaction with host cells, highlighting their potential as postbiotic therapeutics. EcO83‐EVs were isolated, purified, and characterised following the Minimal Information of Studies of Extracellular Vesicles (MISEV) guidelines. Ex vivo studies conducted in human nasal epithelial cells showed that EcO83‐EVs increased the expression of proteins linked to oxidative stress and inflammation, indicating an effective interaction between EVs and the host cells. Further in vivo studies in mice demonstrated that EcO83‐EVs interact with nasal‐associated lymphoid tissue, are internalised by airway macrophages, and stimulate neutrophil recruitment in the lung. Mechanistically, EcO83‐EVs activate the NF‐κΒ signalling pathway, resulting in the nitric oxide production. EcO83‐EVs demonstrate significant potential as a postbiotic alternative to live bacteria, offering a safer option for therapeutic applications. Further research is required to explore their clinical use, particularly in mucosal vaccination and targeted immunotherapy strategies.

Abstract Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial‐mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self‐renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in‐depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC‐mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)‐T cell therapy, cytokine‐induced killer (CIK) cell therapy, natural killer (NK) cell‐mediated CSC‐targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.

Abstract Glacial movements shaped vast northern parts, offering critical insights into glacial dynamics in a changing climate. Located on the island of Rügen in NE Germany, the Jasmund Glacitectonic Complex (JGC) is a key area to study the dynamics of past glaciations. Previous reconstructions focused primarily on the onshore realm, resulting in some areas remaining unexplored. Here we use more than 140 high‐resolution marine multi‐channel seismic profiles to map the erosional unconformity surrounding the JGC for the first time. Submarine glacial features match features observed onshore, allowing a consistent land‐to‐sea reconstruction of the evolution of the JGC. Our results indicate a single SW‐directed Weichselian glacier advance, suggesting that the JGC formed through three distinct glacier lobes exerting pressure from multiple directions. The ice advance encircled the Jasmund peninsula and overthrusted Cretaceous sediments on the JGC perpendicularly and laterally.

Abstract We have constructed a new, simplified constant‐head infiltrometer automated with a self‐contained water level datalogger (HOBO U20L‐01) repurposed to measure changes in gas pressure inside an inverted bottle reservoir. Our field tests of six of these infiltrometers confirmed that recorded changes in gas pressure were strongly correlated with changes in water level in the infiltrometer reservoir (R2 = 0.9998). Further, by using the derived experimental calibration function, we were able to obtain accurate near‐steady‐state infiltration rates. This infiltrometer is cheaper and lighter than current commercially available infiltrometers. It can be easily assembled with materials readily available in most hardware stores, and its user‐friendly datalogger does not require any programming knowledge. This infiltrometer is compatible with various ponding infiltration methods, and its generic design allows for modifications with locally available materials to meet diverse research needs.

Abstract Despite significant progress in the medical field, there is still a pressing need for minimal‐invasive tools to assist with decision‐making, especially in cases of polytrauma. Our team explored the potential of serum‐derived large extracellular vesicles, so called microparticles/microvesicles/ectosomes, to serve as a supportive tool in decision‐making in polytrauma situations. We focused on whether monocyte derived large EVs may differentiate between polytrauma patients with internal organ injury (ISS > 15) and those without. Thus, we compared our EV data to soluble biomarkers such as tumour necrosis factor alpha (TNF alpha) and Interleukin‐8 (IL‐8). From the blood of 25 healthy and 26 patients with polytrauma large EVs were isolated, purified, and characterized. TNF alpha and IL‐8 levels were quantified. We found that levels of these monocyte derived large EVs were significantly higher in polytrauma patients with internal organ damage and correlated with the ISS. Interestingly, we also observed a decline in AnnV+CD14+ large EVs during normal recovery after trauma. Thus, inflammatory serological markers as TNF alpha and as IL‐8 demonstrated an inability to discriminate between polytrauma patients with or without internal organ damage, such as spleen, kidney, or liver lacerations/ruptures. However, TNF and IL‐8 levels were elevated in polytrauma cases overall when contrasted with healthy non‐traumatic controls. These findings suggest that delving deeper into the potential of AnnV+ large EVs derived from monocytes could highly beneficial in the managment of polytrauma, potentially surpassing the efficacy of commonly used serum markers.

Abstract Anthropogenic activities increase the level of dissolved heavy metals in some tropical near‐shore environments threatening reef ecosystems. The skeleton of stony corals like Porites species potentially provides a high‐resolution geochemical archive for past heavy metal concentrations, with potentially century long records revealing baseline values before large‐scale human disturbance. However, few data exist for heavy metal partitioning into coral skeleton aragonite. To address this, culturing experiments exposing Porites lobata and Porites lichen to a mixture of dissolved Cr, Mn, Ni, Cu, Zn, Ag, Cd, Sn, Hg, and Pb over a wide concentration range have been performed. Water samples were taken frequently to monitor changes in the heavy metal concentration. Laser ablation ICP‐MS measurements of the coral aragonite revealed metal concentrations that were positively correlated with Cr, Mn, Ni, Zn, Ag, Cd, and Pb concentrations in seawater. The DTE values for most metals appear dependent on the seawater metal content, approximating a power law, and therefore stabilize at higher seawater metal/Ca ratios. The partitioning of Pb into the coral skeleton is a notable exception, with DPb being stable around 2 to 1 across a large range of “natural” to highly polluted seawater Pb concentrations. This and the general agreement with partition coefficients estimated by previous work suggests that the reconstruction of the heavy metal concentration in seawater for ecosystem monitoring is possible. However, the high variability within and between coral colonies requires further study and suggests that multiple records from multiple coral colonies should be combined to obtain robust reconstructions.

Abstract Chronic pain represents a significant unmet medical need, affecting one‐fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non‐opioid, non‐NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single‐ascending dose (SAD) study and a fed‐fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment‐emergent adverse events were considered related to EC5026. No apparent treatment‐ or dose‐related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near‐dose‐proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5–2 mg doses. Mean half‐lives ranged from 41.8 to 59.1 h. for doses of 8–24 mg, supporting a once‐daily dosing regimen. In the fed‐fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half‐lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Background The congenital heart disease (CHD) population is growing and aging. We aim to examine the impact by describing the temporal trend and causes of lifetime hospitalization burden among the CHD population. Methods and Results From the Danish National Patient Registry, 23 141 patients with CHD and their hospitalizations from 1977 to 2018 were identified, excluding patients with extracardiac malformation. Patients with CHD were categorized into major CHD and minor CHD, and each patient was matched with 10 controls by sex and year of birth. The rate of all‐cause hospitalization increased over time from 28.3 to 36.4 hospitalizations per 100 person‐years (PY) with rate difference (RD) per decade of 2.5 (95% CI, 2.0–3.1) hospitalizations per 100 PY for the patients with CHD, compared with the increase from 10.8 to 17.0 per 100 PY (RD per decade, 2.0 [95% CI, 1.8–2.2] per 100 PY) for the control group (RD for CHD versus control, P=0.08). The all‐cause hospitalization rate remained constant for the major CHDs (RD per decade, −0.2 [95% CI, −1.2 to 0.9] per 100 PY) but increased for the minor CHDs (RD per decade, 5.2 [95% CI, 4.3–6.0] per 100 PY). For all patients with CHD, the cardiovascular hospitalization rate remained constant over time (RD per decade, 0.2 [95% CI, −0.3 to 0.6] per 100 PY) whereas the noncardiovascular hospitalization rate increased (RD per decade, 2.1 [95% CI, 1.6–2.7] per 100 PY). The length of all‐cause hospital stays for all patients with CHD decreased from 2.7 (95% CI, 2.6–2.8) days per PY in 1977 to 1987 to 1.6 (95% CI, 1.6–1.7) days per PY in 2008 to 2018. Conclusions Compared with previous decades, patients with CHD have an increasing hospitalization rate, similar to the general population, but a decreasing length of hospital stay. The increase in hospitalization rate was driven by noncardiovascular hospitalizations, with the patients with minor CHD being the key contributor to the increasing rate.

Post‐translational modifications are key in the regulation of activity, structure, localization, and stability of most proteins in eukaryotes. Phosphorylation is potentially the most studied post‐translational modification, also due to its reversibility and thereby the regulatory role this modification often plays. While most research attention was focused on kinases in the past, phosphatases remain understudied, most probably because the addition and presence of the modification is more easily studied than its removal and absence. Here, we report the identification of an uncharacterized protein tyrosine phosphatase PPH‐7 in C. elegans, a member of the evolutionary conserved PTPN family of phosphatases. Lack of PPH‐7 function led to reduction of fertility and embryonic lethality at elevated temperatures. Proteomics revealed changes in the regulation of targets of the von Hippel–Lindau (VHL) E3 ligase, suggesting a potential role for PPH‐7 in the regulation of VHL.

ABSTRACT Objectives The purpose of this study was to engage key stakeholders in a health research priority‐setting process to identify, prioritize and produce a community‐driven list of research questions addressing intersectional issues on mental health and addictions (MHA) in acquired brain injury (ABI). Methods A multiphasic health research priority‐setting process was co‐designed and executed with community‐based stakeholders, including researchers, health professionals, clinicians, service providers, representatives from brain injury associations, policy makers and people with lived experience of ABI and MHA, including patients and their family members. Stakeholders' ideas led to the generation of research questions, which were prioritized at a 1‐day workshop. Results Fifty‐nine stakeholders participated in the priority‐setting activity during the workshop, which resulted in a rank‐ordered list of the top 10 questions for research addressing the intersections of ABI and MHA. Questions identified touched on several pressing issues (e.g., opioid crisis, homelessness), encompassed multiple subtypes of ABI (e.g., hypoxic‐ischaemic, mild traumatic), and involved different domains (e.g., identification, intervention) of health research. Conclusions This community‐driven health research priority‐setting study identified and prioritized research questions addressing the intersections of ABI and MHA. Researchers and funding agencies should use this list to inform their agendas and address stakeholders' most urgent needs, fostering meaningful improvements to clinical services. Patient or Public Contribution An 11‐person working group comprised of people with lived experience, service providers, researchers, healthcare professionals and other key stakeholders collaboratively developed and informed the scope, design, methodology and interpretation of this study. Over 50 community‐based stakeholders contributed to the research priority‐setting activity. One co‐author is a person with lived experience.

Key Clinical Message After ingestion rubber gloves harden and can produce dangerous complications. Therefore the choice of treatment is of utmost importance. Aside from a surgical approach, endoscopy should also be considered as a treatment option on a case‐to‐case basis or if not applicable as a useful diagnostic tool.

Abstract Climate change is swiftly altering environmental winter conditions, leading to significant ecological impacts such as phenological shifts in many species. As a result, animals might face physiological mismatches due to longer or earlier activity periods and are at risk of being exposed to late spring freezes. Our study points for the first time to the complex physiological challenges that amphibians face as a result of changing thermal conditions due to winter climate change. We investigated the physiological responses to a period of warmer winter days and sudden spring freeze in the common toad (Bufo bufo) by acclimating them to 4°C or 8°C for 48 h or exposing them to 4°C or −2°C for 6 h, respectively. We assessed the daily energy demands, determined body condition and cold tolerance, explored the molecular responses to freezing through hepatic tissue transcriptome analysis, and measured blood glucose levels. Toads acclimated to higher temperatures showed a higher daily energy expenditure and a reduced cold tolerance suggesting faster depletion of energy stores and the loss of winter acclimation during warmer winters. Blood sugar levels were higher in frozen toads indicating the mobilization of cryoprotective glucose with freezing which was further supported by changed patterns in proteins related to glucose metabolism. Overall, our results emphasize that increased thermal variability incurs physiological costs that may reduce energy reserves and thus affect amphibian health and survival. This might pose a serious threat to breeding adults and may have subsequent effects at the population level.

Key Clinical Message In chronic heart failure, dilutional anemia and hypervolemia may occur due to plasma volume expansion, the latter sometimes exacerbated by an increase in red cell volume. Diagnosis and a therapeutic strategy require determination of vascular volumes.

Abstract Sheep and goats of different ages may have to be killed on‐farm for purposes other than slaughter (where slaughter is defined as killing for human consumption) either individually (i.e. on‐farm killing of unproductive, injured or terminally ill animals) or on a large scale (i.e. depopulation for disease control purposes and for other situations, such as environmental contamination and disaster management) outside the slaughterhouses. The purpose of this opinion was to assess the hazards and welfare consequences associated with the on‐farm killing of sheep and goats. The whole killing procedure was divided into Phase 1 (pre‐killing) – that included the processes (i) handling and moving the animals to the killing place and (ii) restraint of the animals before application of the killing methods and Phase 2 – that included stunning and killing of the animals. The killing methods for sheep and goats were grouped into three categories: (1) mechanical, (2) electrical and (3) lethal injection. Welfare consequences that sheep and goats may experience during each process were identified (e.g. handling stress, restriction of movements and tissue lesions during restraint) and animal‐based measures (ABMs) to assess them were proposed. During application of the killing method, sheep and goats will experience pain and fear if they are ineffectively stunned or if they recover consciousness. ABMs related to the state of consciousness can be used to indirectly assess pain and fear. Flowcharts including ABMs for consciousness specific to each killing method were included in the opinion. Possible welfare hazards were identified for each process, together with their origin and related preventive and corrective measures. Outcome tables linking hazards, welfare consequences, ABMs, origins, preventive and corrective measures were developed for each process. Mitigation measures to minimise welfare consequences were proposed.

Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p

Abstract Microbial communities from extreme environments are largely understudied, but are essential as producers of metabolites, including enzymes, for industrial processes. As cultivation of most microorganisms remains a challenge, culture‐independent approaches for enzyme discovery in the form of metagenomics to analyse the genetic potential of a community are rapidly becoming the way forward. This study focused on analysing a metagenome from the cold and alkaline ikaite columns in Greenland, identifying 282 open reading frames (ORFs) that encoded putative carbohydrate‐modifying enzymes with potential applications in, for example detergents and other processes where activity at low temperature and high pH is desired. Seventeen selected ORFs, representing eight enzyme families were synthesized and expressed in two host organisms, Escherichia coli and Aliivibrio wodanis. Aliivibrio wodanis demonstrated expression of a more diverse range of enzyme classes compared to E. coli, emphasizing the importance of alternative expression systems for enzymes from extremophilic microorganisms. To demonstrate the validity of the screening strategy, we chose a recombinantly expressed cellulolytic enzyme from the metagenome for further characterization. The enzyme, Cel240, exhibited close to 40% of its relative activity at low temperatures (4°C) and demonstrated endoglucanase characteristics, with a preference for cellulose substrates. Despite low sequence similarity with known enzymes, computational analysis and structural modelling confirmed its cellulase‐family affiliation. Cel240 displayed activity at low temperatures and good stability at 25°C, activity at alkaline pH and increased activity in the presence of CaCl2, making it a promising candidate for detergent and washing industry applications.

Abstract While macroinvertebrate dispersal operates at the individual level, predictions of their dispersal capabilities often rely on indirect proxies rather than direct measurements. To gain insight into the dispersal of individual specimens, it is crucial to mark (label) and capture individuals. Isotopic enrichment with 15N is a non‐invasive method with the potential of labelling large quantities of macroinvertebrates. While the analysis of 15N is widely utilised in food web studies, knowledge on the specific utility of isotopic enrichment with 15N for mass labelling of macroinvertebrate individuals across different taxa and feeding types is limited. Previous studies have focused on single species and feeding types, leaving gaps in our understanding of the broader applicability of this method. Therefore, this study aimed to test and compare isotopic mass enrichment across several macroinvertebrate taxa and feeding types. We released 15NH4Cl at five stream reaches in North‐Rhine Westphalia, Germany, and successfully enriched 12 distinct macroinvertebrate taxa (Crustacea and Insecta). Significant enrichment was achieved in active and passive filter feeders, grazers, shredders and predators, and predominantly showed positive correlations with the enrichment of the taxa's main food sources phytobenthos and particulate organic matter. Enrichment levels rose rapidly and peaked at distances between 50 m and 300 m downstream of the isotopic inlet; significant enrichment occurred up to 2000 m downstream of the isotopic inlet in all feeding types. Macroinvertebrate density estimates on the stream bottom averaged to a total of approximately 3.4 million labelled individuals of the 12 investigated taxa, thus showing the high potential of isotopic (15N) enrichment as a non‐invasive method applicable for mass labelling across different macroinvertebrate feeding types. Hence, isotopic enrichment can greatly assist the analysis of macroinvertebrate dispersal through mark‐and‐recapture experiments, as it allows to measure the movement at the level of individual specimens.

Abstract In the face of a changing climate, the understanding, predictions, and projections of natural and human systems are increasingly crucial to prepare and cope with extremes and cascading hazards, determine unexpected feedbacks and potential tipping points, inform long‐term adaptation strategies, and guide mitigation approaches. Increasingly complex socio‐economic systems require enhanced predictive information to support advanced practices. Such new predictive challenges drive the need to fully capitalize on ambitious scientific and technological opportunities. These include the unrealized potential for very high‐resolution modeling of global‐to‐local Earth system processes across timescales, reduction of model biases, enhanced integration of human systems and the Earth Systems, better quantification of predictability and uncertainties; expedited science‐to‐service pathways, and co‐production of actionable information with stakeholders. Enabling technological opportunities include exascale computing, advanced data storage, novel observations and powerful data analytics, including artificial intelligence and machine learning. Looking to generate community discussions on how to accelerate progress on U.S. climate predictions and projections, representatives of Federally‐funded U.S. modeling groups outline here perspectives on a six‐pillar national approach grounded in climate science that builds on the strengths of the U.S. modeling community and agency goals. This calls for an unprecedented level of coordination to capitalize on transformative opportunities, augmenting and complementing current modeling center capabilities and plans to support agency missions. Tangible outcomes include projections with horizontal spatial resolutions finer than 10 km, representing extremes and associated risks in greater detail, reduced model errors, better predictability estimates, and more customized projections to support next generation climate services.

Abstract The dynamics shaping the El Niño‐Southern Oscillation's (ENSO) response to present and future climate change remain unclear, partly due to limited paleo‐ENSO records spanning past abrupt climate events. Here, we measure Mg/Ca ratios on individual foraminifera to reconstruct east Pacific subsurface temperature variability, a proxy for ENSO variability, across the last 25,000 years, including the millennial‐scale events of the last deglaciation. Combining these data with proxy system model output reveals divergent ENSO responses to Northern Hemisphere stadials: enhanced variability during Heinrich Stadial 1 (H1) and reduced variability during the Younger Dryas (YD), relative to the Holocene. H1 ENSO likely intensified through meltwater‐induced changes to ocean/atmospheric circulation, a response observed in models, but the lack of a similar response during the YD challenges model simulations. We suggest the tropical Pacific mean state during H1 primed ENSO for larger fluctuations under meltwater forcing, whereas the YD mean state likely buffered against it.

Abstract Objectives Olfactory training (OT) has emerged as a first‐line therapeutic approach to the management of olfactory dysfunction. Conventional OT (COT) involves the systematic home‐based exposure to four distinct odors. Previous research has demonstrated that immersive OT (IOT) involving full‐body exposure to dozens of distinct odors could also improve overall olfactory function. This study compared IOT and COT in terms of efficacy. Methods A total of 60 patients were enrolled and assigned to three groups. The IOT group (n = 25) underwent immersive exposure to 64 odors once daily in a specialized theater. COT participants (n = 17) sniffed four typical odors in a set of four jars twice daily at home. A control group (n = 18) underwent passive observation. Olfactory function was assessed before and after training. Results Significant improvements in composite threshold‐discrimination‐identification (TDI) scores were observed after training in both the IOT (mean difference = 2.5 ± 1.1. p = .030) and COT (mean difference = 4.2 ± 1.3, p = .002) groups. No changes were observed in the control group. A significantly higher proportion of patients in the COT group (41%) presented improvements of clinical importance (TDI ≥5.5) compared to the controls (p = .018). The improvements attained in the IOT group (20%) were less pronounced (p = .38). Conclusion While IOT did not exhibit the same efficacy as COT in restoring olfactory function, it still demonstrated promising outcomes. Future efforts to advance olfactory recovery should focus on cross‐modal integration. Level of Evidence Level 3.

Abstract Field application of beef cattle feedlot runoff may transport manure‐borne microbes and antibiotic resistant bacteria to agricultural soils eventually impacting deeper soils and groundwater. To evaluate this potential, total soil, antibiotic resistance (AR), and fecal indicator bacteria (Escherichia coli and Enterococcus) and the presence/abundance of AR genes were examined to a depth of 1.8 m in an agricultural field receiving long‐term application of feedlot runoff and compared to a nearby pasture receiving no runoff. While plate counts of total soil bacteria and cefotaxime‐resistant, erythromycin‐resistant, and tetracycline‐resistant bacteria decreased with depth on both fields (p

Abstract Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X‐linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X‐linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X‐linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X‐linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X‐linked TSGs in sex chromosome–autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X‐linked TSG in immunomodulation and in gender‐based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X‐linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

Abstract Poloxamers are amphiphilic block copolymers consisting of poly(ethylene glycol) (PEG) and poly(propylene glycol) segments. Their self‐assembly and interfacial properties are tied to the relative hydrophilicity and hydrophobicity of each block and can therefore be adjusted by changing block lengths. Here, a series of PEG‐polycycloether block copolymers is synthesized that have the same structure as a poloxamer, but they encompass a rigid polycyclic backbone as the hydrophobic block. A variety of polymer structures are synthesized, for example diblock or triblock architectures, with/without olefinic units, atactic or isotactic backbone, and different block lengths. Due to their amphiphilicity, self‐assembly into spherical aggregates (diameters ranging from 64 to 132 nm) at low concentrations (critical aggregation concentration as low as 0.04 mg mL−1) is observed in water. Low surface tensions (as low as 26.7 mN m−1) are observed as well as the formation of stable high internal phase emulsions (HIPEs) irrespective of the oil/water ratio. This contrasts with the properties of the commonly used poloxamers P188 or P407 and illustrates the significance of the rigid polycycloether block. These new colloidal properties offer new prospects for applications in emulsion formulations for biomedicine, cosmetics, and the food industry.

Abstract Background Inhibition of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans. Hypothesis/Objective Determine if molidustat, a novel HIF‐PH inhibitor, stimulates erythropoiesis in healthy cats. Animals Seventeen healthy adult laboratory cats. Methods Randomized, placebo‐controlled study. Cats were treated PO once daily with suspensions of 0 (Group 1; n = 6), 5 (Group 2; n = 6), or 10 (Group 3; n = 5) mg/kg of molidustat. Effects on red blood cell parameters, reticulocyte indices and plasma erythropoietin (EPO) concentrations were evaluated. Molidustat treatment was stopped when hematocrit (HCT) exceeded 60%. Results Compared to placebo, a significant increase in mean HCT was evident starting on Day 14 (Group 2:54.4% vs 40.3%, P

Abstract Free heme is released from hemoproteins during hemolysis or ischemia reperfusion injury and can be pro‐inflammatory. Most studies on nephrotoxicity of hemolysis‐derived proteins focus on free hemoglobin (fHb) with heme as a prosthetic group. Measurement of heme in its free, non‐protein bound, form is challenging and not commonly used in clinical routine diagnostics. In contrast to fHb, the role of free heme in acute kidney injury (AKI) after cardiopulmonary bypass (CPB) surgery is unknown. Using an apo‐horseradish peroxidase‐based assay, we identified free heme during CPB surgery as predictor of AKI in patients undergoing cardiac valve replacement (n = 37). Free heme levels during CPB surgery correlated with depletion of hemopexin (Hx), a heme scavenger‐protein. In mice, the impact of high levels of circulating free heme on the development of AKI following transient renal ischemia and the therapeutic potential of Hx were investigated. C57BL/6 mice were subjected to bilateral renal ischemia/reperfusion injury for 15 min which did not cause AKI. However, additional administration of free heme in this model promoted overt AKI with reduced renal function, increased renal inflammation, and reduced renal perfusion on functional magnetic resonance imaging. Hx treatment attenuated AKI. Free heme administration to sham operated control mice did not cause AKI. In conclusion, free heme is a predictor of AKI in CPB surgery patients and promotes AKI in transient renal ischemia. Depletion of Hx in CPB surgery patients and attenuation of AKI by Hx in the in vivo model encourage further research on Hx therapy in patients with increased free heme levels during CPB surgery.

Abstract Sedimentary ancient DNA (sedaDNA) offers an important opportunity for investigating long‐term community dynamics. Nevertheless, sedaDNA is challenging since DNA is degraded and fragmented over time. Of particular interest for such sedaDNA studies are phytoplankton communities, which are sensitive environmental indicators and important producers in aquatic systems. So far, only a few suitable metabarcoding primers for sedaDNA targeting phytoplankton exist. In this study, we introduce new metabarcoding primers targeting cyanobacteria and dinoflagellates. They amplify short, ~200‐bp ribosomal 16S and 18S DNA fragments. We compared these primers against published ones, uncovering distinct communities captured by different primer sets. The newly designed dinoflagellate and cyanobacterial primers revealed unique sets of amplicon sequence variants (ASVs) compared to published primers, highlighting the impact of primer choice on describing community composition. We also explored the effect of amplicon length on metabarcoding success over a sample age. Observed trends suggest that amplification success decreases with longer amplicons, probably as a result of DNA degradation in older sediment samples. Lastly, strong DNA preservation challenges emerged in sediment samples older than 7000 BP, corresponding with oxic phases of the Baltic Sea bottom water. This emphasizes the importance of age, sediment type, and preservation conditions when interpreting sedaDNA results. Despite limitations in temporal resolution, the study shows that sedaDNA‐based fluctuations in the phytoplankton community are consistent with well‐known environmental stages. More research is necessary to understand (1) DNA preservation and its impact on reconstructed communities and (2) impact of abiotic conditions on phytoplankton communities.