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Societal Impact Statement The invasive species S. alterniflora and P. australis are fast growing coastal wetland plants sequestering large amounts of carbon in the soil and protect coastlines against erosion and storm surges. In this global analysis, we found that Spartina and Phragmites increase methane but not nitrous oxide emissions, with Phragmites having a lesser effect. The impact of the invasive species on emissions differed greatly among different types of native plant groups, providing valuable information to managers and policymakers during coastal wetland planning and restoration efforts. Further, our estimated net emissions per wetland plant group facilitate regional and national blue carbon estimates. Summary Globally, Spartina alterniflora and Phragmites australis are among the most pervasive invasive plants in coastal wetland ecosystems. Both species sequester large amounts of atmospheric carbon dioxide (CO2) and biogenic carbon in soils but also support production and emission of methane (CH4). In this study, we investigated the magnitude of their net greenhouse gas (GHG) release from invaded and non‐invaded habitats. We conducted a meta‐analysis of GHG fluxes associated with these two species and related soil carbon content and plant biomass in invaded coastal wetlands. Our results show that both invasive species increase CH4 fluxes compared to uninvaded coastal wetlands, but they do not significantly affect CO2 and N2O fluxes. The magnitude of emissions from Spartina and Phragmites differs among native habitats. GHG fluxes, soil carbon and plant biomass of Spartina‐invaded habitats were highest compared to uninvaded mudflats and succulent forb‐dominated wetlands, while being lower compared to uninvaded mangroves (except for CH4). This meta‐analysis highlights the important role of individual plant traits as drivers of change by invasive species on plant‐mediated carbon cycles.

Abstract Objective To systematically evaluate which lesion‐based imaging features and methods allow for the best statistical prediction of poststroke deficits across independent datasets. Methods We utilized imaging and clinical data from three independent datasets of patients experiencing acute stroke (N1 = 109, N2 = 638, N3 = 794) to statistically predict acute stroke severity (NIHSS) based on lesion volume, lesion location, and structural and functional disconnection with the lesion location using normative connectomes. Results We found that prediction models trained on small single‐center datasets could perform well using within‐dataset cross‐validation, but results did not generalize to independent datasets (median R2N1 = 0.2%). Performance across independent datasets improved using large single‐center training data (R2N2 = 15.8%) and improved further using multicenter training data (R2N3 = 24.4%). These results were consistent across lesion attributes and prediction models. Including either structural or functional disconnection in the models outperformed prediction based on volume or location alone (P

Abstract Background The tumor microenvironment (TME), including infiltrating T‐cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death‐1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B‐cell lymphoma. Methods Adults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200 mg IV in 21‐day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)‐positron emission tomography‐computed tomography (PET‐CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1. Results Nine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high‐tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET‐CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow‐up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune‐related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected. Conclusion Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.

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 Aim Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re‐hospitalization and death. Mid‐regional pro‐adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure. Methods and results Observational, prospective, single‐centre study in unselected patients presenting with acute heart failure. This study aimed to assess adrenomedullin's association with congestion and clinical outcomes: in‐hospital death, post‐discharge mortality and in‐hospital worsening heart failure according to RELAX‐AHF‐2 trial criteria. Pro‐adrenomedullin was quantified at baseline and at discharge. Congestion was assessed applying clinical scores. Cox and logistic regression models with adjustment for clinical features were fitted. N = 233, median age 77 years (IQR 67, 83), 148 male (63.5%). Median pro‐adrenomedullin 2.0 nmol/L (IQR 1.4, 2.9). Eight patients (3.5%) died in hospital and 100 (44.1%) experienced in‐hospital worsening heart failure. After discharge, 60 patients (36.6%) died over a median follow‐up of 1.92 years (95% CI: 1.76, 2.46). Pro‐adrenomedullin concentrations (logarithmized) were significantly associated with congestion, both at enrolment (β = 0.36 and 0.81 depending on score, each P

Abstract Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. Study Design The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow‐up. Three hundred patients, aged 18–75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I–III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high‐density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. Discussion The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.

The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E‐mutated GBM benefit from BRAF/MEK‐inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (

Abstract Background Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown. Hypothesis We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats. Animals Ten domestic cats. Methods In this 2‐sequence, 2‐period, 2‐treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2‐week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high‐performance liquid chromatography‐tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer‐100 (PFA‐100). Results Multiplate Analyzer and PFA‐100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P

Abstract Understanding the patterns of marine microbial diversity (Bacteria + Archaea) is essential, as variations in their alpha‐ and beta‐diversities can affect ecological processes. Investigations of microbial diversity from global oceanographic expeditions and basin‐wide transects show positive correlations between microbial diversity and either temperature or productivity, but these studies rarely captured seasonality, especially in polar regions. Here, using multiannual alpha‐diversity data from eight time series in the northern and southern hemispheres, we show that marine microbial community richness and evenness generally correlate more strongly with daylength than with temperature or chlorophyll a (a proxy for photosynthetic biomass). This pattern is observable across time series found in the northern and southern hemispheres regardless of collection method, DNA extraction protocols, targeted 16S rRNA hypervariable region, sequencing technology, or bioinformatics pipeline.

Abstract Objective Anti‐CD20 therapy is a highly effective treatment for multiple sclerosis (MS). In this study, we investigated MS‐related changes in peripheral blood mononuclear cell (PBMC) subsets compared to healthy controls and longitudinal changes related to the treatment. Methods Multicolor spectral flow cytometry analysis was performed on 78 samples to characterize disease‐ and treatment‐related PBMC clusters. Blood samples from MS patients were collected at baseline and up to 8 months post‐treatment, with three collection points after treatment initiation. Unsupervised clustering tools and manual gating were applied to identify subclusters of interest and quantify changes. Results B cells were depleted from the periphery after anti‐CD20 treatment as expected, and we observed an isolated acute, transitory drop in the proportion of natural killer (NK) and NKT cells among the main populations of PBMC (P = 0.03, P = 0.004). Major affected PBMC subpopulations were cytotoxic immune cells (NK, NKT, and CD8+ T cells), and we observed a higher proportion of cytotoxic cells with reduced brain‐homing ability and a higher regulatory function as a long‐term anti‐CD20‐related effect. Additionally, anti‐CD20 therapy altered distributions of memory CD8+ T cells and reduced exhaustion markers in both CD4+ and CD8+ T cells. Interpretation The findings of this study elucidate phenotypic clusters of NK and CD8+ T cells, which have previously been underexplored in the context of anti‐CD20 therapy. Phenotypic modifications towards a more regulatory and controlled phenotype suggest that these subpopulations may play a critical and previously unrecognized role in mediating the therapeutic efficacy of anti‐CD20 treatments.

Abstract Aims Individuals with congenital heart disease (CHD) are at an increased risk for cancer. As cancer survival rates improve, the prevalence of late side effects, such as heart failure (HF), is becoming more evident. This study aims to evaluate the risk of developing HF following a cancer diagnosis in patients with CHD, compared with those without CHD and with CHD patients who do not have cancer. Methods CHD patients (n = 69 799) and randomly selected non‐CHD controls (n = 650 406), born in Sweden between 1952 and 2017, were identified from the Swedish National Health Registers and Total Population Register (excluding those with syndromes and transplant recipients). CHD patients who developed cancer (n = 1309) were propensity score‐matched with non‐CHD patients who developed cancer (n = 9425), resulting in a cohort of 1232 CHD patients with cancer and 2602 non‐CHD controls with cancer (after exclusion of individuals with HF prior to cancer diagnosis). In a separate analysis, CHD patients with cancer were propensity score‐matched with CHD patients without cancer (n = 68 490). A total of 1233 CHD patients with cancer and 2257 CHD patients without cancer were included in the study. Results Among CHD patients with cancer, 73 (5.9%) developed HF during a mean follow‐up time of 8.5 ± 8.7. Comparatively, in the propensity‐matched control population, 29 (1.1%) non‐CHD cancer patients (mean follow‐up time of 7.3 ± 7.5) and 101 (4.5%) CHD patients without cancer (mean follow‐up time of 9.9 ± 9.2) developed HF. CHD patients exhibited a significantly higher risk of HF post‐cancer diagnosis compared with the non‐CHD control group [hazard ratio (HR) 4.39, 95% confidence interval (CI) 2.83–6.81], after adjusting for age at cancer diagnosis and comorbidities. In the analysis between CHD patients with cancer and those without cancer, the results indicated a significantly higher risk of developing HF in CHD patients with cancer (HR 1.53, 95% CI 1.13–2.07). Conclusions CHD patients face a more than four‐fold increased risk of developing HF after a cancer diagnosis compared with cancer patients without CHD. Among CHD patients, the risk of HF is only modestly higher for those with cancer than for those without cancer. This suggests that the increased HF risk in CHD patients with cancer, relative to non‐CHD cancer patients, may be more attributable to CHD itself than to cancer treatment‐related side effects.

Abstract Introduction Magnetic resonance imaging (MRI) is a rapidly evolving modality, generally considered safe due to lack of ionising radiation. While MRI technology and techniques are improving, many of the safety concerns remain the same as when first established. Patient thermal injuries are the most frequently reported adverse event, accounting for 59% of MRI incidents to the Food and Drug Administration (FDA). Surveys indicate many incidents remain unreported. Patient thermal injuries are preventable and various methods for their mitigation have been published. However, recommendations can be variable, fragmented and confusing. The aim of this systematic review was to synthesise the evidence on MRI safety and associated skin injuries and offer comprehensive recommendations for radiographers to prevent skin thermal injuries. Methods Four journal databases were searched for sources published January 2010–May 2023, presenting information on MRI safety and thermal injuries. Results Of 26,801 articles returned, after careful screening and based on the eligibility criteria, only 79 articles and an additional 19 grey literature sources were included (n = 98). Included studies were examined using thematic analysis to determine if holistic recommendations can be provided to assist in preventing skin burns. This resulted in three simplified recommendations: Remove any electrically conductive items Insulate the patient to prevent any conductive loops or contact with objects Communicate regularly Conclusion By implementing the above recommendations, it is estimated that 97% of skin burns could be prevented. With thermal injuries continuing to impact MRI safety, strategies to prevent skin burns and heating are essential. Assessing individual risks, rather than blanket policies, will help prevent skin thermal injuries occurring, improving patient care.

Abstract Objective The objective of the study is to characterize the pathomechanisms underlying actininopathies. Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begin in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2, have been shown to cause distal myopathy. ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha‐actinin‐2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha‐actinin‐2 is to link actin and titin to the sarcomere Z‐disk. New ACTN2 variants are continuously discovered; however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype–phenotype correlations in ACTN2‐related diseases, actininopathies, persists. Methods Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies. We assess the genotype–phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha‐actinin‐2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do form alpha‐actinin‐2 aggregates. Interpretation The results suggest that alpha‐actinin‐2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein‐extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

Abstract Objective The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). Methods We included 160 patients with a first‐ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. Results According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). Interpretation According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

Objective Our objective was to describe the administration of glucocorticoids (GCs) and characterize its association with organ damage in a longitudinal systemic lupus erythematosus (SLE) cohort over a time period spanning the introduction of biologics in Canada. Methods A retrospective observational study was conducted using data from a large SLE cohort in Canada, including adults without lupus nephritis or central nervous system lupus. Patients were observed from time of entry into the cohort to the last available clinic visit (up to December 31, 2020), with a minimum of 24 months of follow‐up. Demographic and clinical characteristics, including average disease activity, treatment administration, and prevalence of organ damage, were examined. Organ damage was stratified by GC administration. Results A total of 1,255 patients were included. The mean follow‐up duration was 10.5 (SD 8.6) years. One hundred eighty‐two (15%) patients had organ damage at baseline. More than 80% of patients were prescribed GCs over the follow‐up period, almost all patients had long‐term GC treatment, and only 5% of patients took any biologics. Organ damage was more frequent in patients with a higher average GC dose and greater years of GC exposure. Conclusion In this large cohort of patients with SLE, the majority of patients continue to rely on GC for SLE symptom management, with limited administration of biologics. GC administration was correlated with increased irreversible organ damage. Access to novel GC‐sparing treatment options is critical to improve long‐term outcomes for patients with SLE, especially given the continued reliance on GC despite the introduction of biologics.

The one‐carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)‐ and DNA‐dependent protein kinase (DNA‐PK)‐dependent manner. Furthermore, repair of IR‐induced DNA double‐strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR‐induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2‐depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy.

Abstract Background Reports of leptospirosis in horses are limited. Objectives To describe the clinical and diagnostic findings of acute systemic leptospirosis in horses. Animals Eleven client‐owned horses presented to an equine hospital because of acute onset of disease between 2015 and 2023. Methods Retrospective case series. Horses diagnosed with leptospirosis by 1 or more of urine PCR, serologic microscopic agglutination test (MAT), and histopathology. Results Common clinical signs included lethargy (10), anorexia (10), fever (9), tachypnea (9), abnormal lung sounds (9), and epistaxis (6). Acute kidney injury was present in all cases. Evidence of pulmonary hemorrhage and liver disease was found in 8 (73%) and 6 (55%) horses, respectively. In 6 (55%) horses, kidneys, lungs, and liver were affected. Urine quantitative polymerase chain reaction for detection of pathogenic Leptospira spp. was positive in 6 (55%) cases. On serology Leptospira interrogans serovar Australis, Autumnalis, and Bratislava accounted for 86% of all titers ≥1 : 800. Overall case fatality rate was 4/11 (36%). Main findings on necropsy were tubular necrosis, interstitial nephritis, hemorrhage in the alveoli, pulmonary edema, periportal hepatitis and necrosis, cholestasis, and cholangitis. Conclusions and Clinical Importance Leptospirosis should be considered as a differential diagnosis in horses with evidence of acute systemic inflammation and acute renal injury, epistaxis, or hepatic disease. For increased likelihood of identifying positive cases, both MAT serology and urine PCR should be performed.

Abstract In the current WHO classification, a T‐cell prolymphocytic leukemia (T‐PLL) diagnosis requires lymphocytosis of >5 × 109/L, evidence of monoclonality, and TCL1A or MTCP1 rearrangement. However, the 2019 consensus document suggested that in the absence of rearrangement of TCL1‐family, the presence of abnormalities involving chromosome 11 (11q22.3; ATM), chromosome 8 (idic(8)(p11), t(8;8), trisomy 8q), 5, 12, 13, 22, or a complex karyotype, as well as involvement specific sites (e.g., splenomegaly, effusions) would suffice for a diagnosis of T‐PLL. We present a patient diagnosed with T‐PLL with MTCP1 rearrangement who was successfully treated with alemtuzumab followed by consolidative allogeneic unrelated donor stem cell transplantation. Eight years later, the patient presented with inguinal lymphadenopathy with features more akin to peripheral T‐cell lymphoma, NOS (PTCL, NOS) of the GATA3 subtype, and there was no evidence of peripheral blood involvement. However, the lymphoma cells were clonally related to those at presentation. Currently, literature on T‐PLL‐like cases lacking the rearrangement of TCL1A is limited, and the possibility of whether a proportion of such cases could represent PTCL, NOS (with leukemic involvement) needs consideration.

Abstract Aims Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new‐onset CS in patients hospitalized for AHF. Methods and results Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow‐up until death or discharge. WHF was defined by the RELAX‐AHF‐2 criteria. CS was defined as SCAI stages B–E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In‐hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21–36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32–231.81, P

Abstract Terrestrial groundwater travels through subterranean estuaries before reaching the sea. Groundwater‐derived nutrients drive coastal water quality, primary production, and eutrophication. We determined how dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP), and dissolved organic nitrogen (DON) are transformed within subterranean estuaries and estimated submarine groundwater discharge (SGD) nutrient loads compiling > 10,000 groundwater samples from 216 sites worldwide. Nutrients exhibited complex, nonconservative behavior in subterranean estuaries. Fresh groundwater DIN and DIP are usually produced, and DON is consumed during transport. Median total SGD (saline and fresh) fluxes globally were 5.4, 2.6, and 0.18 Tmol yr−1 for DIN, DON, and DIP, respectively. Despite large natural variability, total SGD fluxes likely exceed global riverine nutrient export. Fresh SGD is a small source of new nutrients, but saline SGD is an important source of mostly recycled nutrients. Nutrients exported via SGD via subterranean estuaries are critical to coastal biogeochemistry and a significant nutrient source to the oceans.

Abstract This study investigated the potential of different wheat varieties to influence the performance of the subsequent wheat crop. In fall 2021, a single variety of winter wheat (cv. Norwest Tandem) was planted into standing wheat stubble in plots that were previously planted to five winter wheat varieties. At harvest, yield was significantly affected by the variety that had been planted in each plot during the first year of the trial. Specifically, wheat following the variety Pritchett yielded approximately 12% more than wheat following the variety Bobtail. While planting the second crop, residue from the winter wheat variety Norwest Duet caused the no‐till plot drill to plug (accumulate large amounts of soil and crop residue in front of openers) far more than residue from the other varieties. This indicates that varieties differ in their residue management requirements. These differences could be exploited to best fit different agricultural practices. This study highlights the potential importance of varietal effects that persist in the field after the field is harvested. However, more work is needed to understand varietal differences in residue management requirements and varietal effects of the successive crop before they can be fully leveraged in wheat breeding and genetics, wheat agronomy, variety testing programs, and eventually the producer's field.

Abstract The Food and Drug Administration's recent decision to eliminate mandatory animal testing for drug approval marks a significant shift to alternative methods. Similarly, the European Parliament is advocating for a faster transition, reflecting public preference for animal‐free research practices. In vitro tissue models are increasingly recognized as valuable tools for regulatory assessments before clinical trials, in line with the 3R principles (Replace, Reduce, Refine). Despite their potential, barriers such as the need for standardization, availability, and cost hinder their widespread adoption. To address these challenges, the Robotic Enabled Biological Automation (ReBiA) system is developed. This system uses a dual‐arm robot capable of standardizing laboratory processes within a closed automated environment, translating manual processes into automated ones. This reduces the need for process‐specific developments, making in vitro tissue models more consistent and cost‐effective. ReBiA's performance is demonstrated through producing human reconstructed epidermis, human airway epithelial models, and human intestinal organoids. Analyses confirm that these models match the morphology and protein expression of manually prepared and native tissues, with similar cell viability. These successes highlight ReBiA's potential to lower barriers to broader adoption of in vitro tissue models, supporting a shift toward more ethical and advanced research methods.

Background The association between raised pulmonary artery pressures, pulmonary vascular resistance (PVR), and right‐sided heart dysfunction is well recognized. The added value of pulsatile indices, specifically pulmonary arterial compliance (PAC) and characteristic impedance, remains unclear. This study aimed to identify the optimal vascular afterload model for predicting right‐sided heart dysfunction in newly diagnosed pulmonary hypertension (PH). METHODS AND RESULTS This was a prospective cohort study of 86 patients with suspected PH (60±16 years; 66 women) who underwent right‐sided heart catheterization and cardiac magnetic resonance imaging. Right ventricular end‐diastolic volume index (RVEDVi) and right atrial (RA) volume index were measured using cardiac magnetic resonance imaging. Vascular resistance, PAC, and characteristic impedance were measured using pulmonary artery pressure from right‐sided heart catheterization and pulmonary artery flow from cardiac magnetic resonance imaging. Optimal model fit was determined by the lowest Akaike Information Criterion value. A total of 58% of patients had a right ventricular ejection fraction

Abstract Artificial intelligence (AI) has the potential to transform clinical practice and healthcare. Following impressive advancements in fields such as computer vision and medical imaging, AI is poised to drive changes in microbiome‐based healthcare while facing challenges specific to the field. This review describes the state‐of‐the‐art use of AI in microbiome‐related healthcare. It points out limitations across topics such as data handling, AI modelling and safeguarding patient privacy. Furthermore, we indicate how these current shortcomings could be overcome in the future and discuss the influence and opportunities of increasingly complex data on microbiome‐based healthcare.

ABSTRACT Objective To evaluate the validity of the Utah statewide All‐Payer Claims Database (APCD), we compared breast cancer‐specific treatments and dosages with gold‐standard abstraction of medical records. Study Design In this pilot study, breast cancer treatments were abstracted by a certified tumor registrar at the Utah Cancer Registry (UCR) for patients diagnosed in 2013 with breast cancer. The abstraction of medical records was the gold standard for comparison with treatments identified in the APCD. The reliability and agreement between the treatment identified in the APCD and abstraction data were measured with sensitivity and specificity. Dose consistency was measured with the intraclass correlation coefficients (ICC). Results Compared with the 186 abstractions, the sensitivity of the APCD to identify chemotherapy agents was high: 89% for any agent, 91% for carboplatin, 83% for docetaxel, 82% for doxorubicin, or 94.7% for biologic therapy. The consistency between the chemotherapy dosage identified in the claims and the abstraction varied from 63% to 76%. For radiotherapy, the sensitivity of the claims to identify the completed radiotherapy regimen was 66%. The ICC between radiotherapy doses identified in the claims and the abstraction was 54% (95% confidence interval [CI], 48%, 67%). Conclusions Employing these novel methods, the claims were highly reliable in identifying cancer treatment agents overall, namely carboplatin, docetaxel, and trastuzumab. The claims were of moderate utility in capturing the treatment dose information. In addition to the APCD, the use of multiple data sources improved the completeness of cancer treatment information.

Abstract “Medical scientists” are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scientists in Germany face limited long‐term career prospects and a lack of dedicated training and support programmes. They also face time limits on their career progression arising from national academic employment legislation, and imminent reforms by the German government are likely to make this worse. Nevertheless, recent developments in the educational landscape including the introduction of increasingly focused MSc, pre‐PhD, and doctoral programmes to train medically aware basic scientists, as well as improved general recognition of the roles and relevance of medical scientists in health research, are encouraging. Physiologists have taken essential steps to improve the recognition of medical scientists in Germany by introducing a “specialist physiologist” qualification; this initiative could be applied to support medical scientists in other fields and countries. In this review, we describe the particular challenges facing medical scientists in Germany and make recommendations that may apply to other academic systems.

Background There is strong interest in the evaluation of longer‐term outcome metrics for congenital heart diseases (CHDs); however, registries focus on postoperative metrics. Methods and Results Informed by user online discussion forums and scoping of national data, we selected sentinel CHDs and long‐term outcome metrics suitable for routine monitoring. We then developed sentinel CHD phenotypes and algorithms for identifying treatment pathway procedures using clinical codes. Finally, we calculated the metrics within a retrospective national cohort analysis. The 9 selected sentinel CHDs had a higher‐than‐average prevalence, typically involved surgery in infancy, and were associated with an increased risk of late mortality. The selected metrics of survival and reinterventions at 1, 5, and 10 years were both important and feasible. The cohort included 29 319 (41.3% of all operated CHD births) English and Welsh children born with sentinel CHDs in 2000 to 2022. Example metrics at age 10 years included: survival—hypoplastic left heart syndrome: 57.6% (95% CI, 54.9%–60.4%), functionally univentricular heart: 86.7% (95% CI, 84.6%–88.9%), transposition of the great arteries: 93.1% (95% CI, 92.2%–93.9%), pulmonary atresia: 81.0% (95% CI, 79.1%–82.9%), atrioventricular septal defect: 88.5% (95% CI, 87.5%–89.5%), tetralogy of Fallot: 95.1% (95% CI, 94.4%–95.8%), aortic stenosis: 94.4% (95% CI, 93.3%–95.6%), coarctation: 96.7% (95% CI, 96.2%–97.3%), and ventricular septal defect: 96.9% 95% CI, (96.4%–97.3%); and (2) cumulative incidence of reintervention—hypoplastic left heart syndrome : 54.5% (95% CI, 51.5%–57.3%), functionally univentricular heart: 57.3% (95% CI, 53.9%–60.5%), transposition of the great arteries: 20.9% (95% CI, 19.5%–22.3%), pulmonary atresia: 66.8% (95% CI, 64.2%–69.1%), atrioventricular septal defect: 21.6% (20.3%–23.0%), tetralogy of Fallot: 26.6% (95% CI, 25.2%–28.0%), aortic stenosis: 31.2% (95% CI, 28.8%–33.6%), coarctation: 19.8% (95% CI, 18.6%–21.1%), and ventricular septal defect: 6.1% (95% CI, 5.5%–6.8%). Conclusions It is feasible to report important long‐term outcomes of survival and reintervention for sentinel CHDs using routinely collected procedure records, adding value to national audit.

Background In the management of acute ischemic stroke, computed tomography perfusion (CTP) is used to define the ischemic core and penumbra to estimate tissue fate after reperfusion therapy. The core/penumbra dichotomy uses single‐value thresholds, which potentially discards valuable data and oversimplifies the complexity of core and penumbral estimation. Advancing the dichotomous CTP output to a probability model has several advantages such as more sophisticated modeling of pathophysiology, supporting reader interpretation, and assessing a greater range of available data to estimate tissue fate. Methods In this retrospective study, we developed a CTP probability model to move away from single perfusion thresholds to estimate tissue fate. All patients from the International Stroke Perfusion Imaging Registry database had baseline CTP and were included in the current study if they had a large vessel occlusion that recanalized fully after thrombectomy and had follow‐up diffusion‐weighted imaging. Data were split into training, validation, and testing groups. Training and validation cohorts were used to develop a deep learning model in project MONAI (Medical Open Network for Artificial Intelligence) and performance metrics were derived from the testing set. Results In total, 243 patients were included in the study. The Attention U‐Net was the best performing deep learning model, producing the best prediction of follow‐up infarct core on the test set (n = 48): mean diverse counterfactual explanations score = 0.430±0.213, mean area under the curve = 0.765±0.095; better than the single‐value thresholding with a diverse counterfactual explanations scoreof 0.247±0.167 (paired t‐test, P

ABSTRACT Introduction We present a relationship‐centred shared‐decision‐making (RCSDM) process model to explicate factors that shape decision‐making processes during physical medicine and rehabilitation (PMR) encounters among patients, their care partners and practitioners. Existing shared decision‐making (SDM) models fall short in addressing the everyday decisions routinely made regarding persons with chronic disabilities who require high levels of support, their care partners and rehabilitation practitioners. In PMR, these everyday decisions are small scale, immediate and in service to a larger therapeutic goal. They can be thought of as micro‐decisions and involve multiple practitioners, care partners and patients. How micro‐decisions are made in this context is contingent on multiple roles and relationships among these relevant parties. Our model centres on micro‐decisions among patients, their care partners and practitioners based on our disorders of consciousness (DoC) research. Methods To develop our model, we examined peer‐reviewed literature in SDM in PMR, chronic disability and person‐centeredness; formed collaborations and co‐created our constructs with rehabilitation practitioners and with care partners who have lived experience of caring for persons with DoC; analysed emerging empirical data and vetted early versions with expert scientific and clinical audiences. Our model builds from the core tenets of relational autonomy, and scholarship and activism of disability advocates. Findings Our model conceptualizes four non‐hierarchical levels of analysis to understand the process of micro‐decision‐making in chronic disability and medical rehabilitation: social forces (historical and sociological); roles and relationships (multiple and intersecting); relational dimensions (interactional and contextual) and micro‐decision moments (initiation, response and closure). Discussion Relationships among patients, their care partners and practitioners are the intersubjective milieu within which decisions are made. Our conceptual model explicates the process of micro‐decision‐making in PMR. Patient or Public Contribution Care partners (or caregivers) and rehabilitation practitioners are active members of our team. We work together to develop research projects, collect, analyse and disseminate data. The conceptual model we present in this manuscript was co‐created—input from care partners and practitioners on previously collected data became the impetus to develop the RCSDM process model and share co‐authorship in this manuscript.

Abstract Tinea capitis is a prevalent dermatophyte infection among German children, primarily caused by Microsporum canis, Trichophyton mentagrophytes and Trichophyton benhamiae. Other pathogens, such as T. soudanense and M. audouinii, have also been identified in Germany. This case report describes a 10‐year‐old Angolan girl with chronic osteomyelitis who was brought to Germany for treatment, which was organized by the Friedensdorf International (Peacevillage International). In addition to chronic osteomyelitis of the lower leg, the patient presented with alopecic areas of the scalp with adherent scales, which raised the suspicion of tinea capitis. Fungal cultivation and polymerase chain reaction (PCR) diagnostics revealed a coinfection of T. soudanense and M. audouinii, which, to the best of our knowledge, has not been previously reported in Europe. After 4 weeks of systemic terbinafine treatment and topical use of ciclopirox solution and clotrimazole cream, there was a marked improvement in the patient's condition. This was confirmed by a negative fungal culture and PCR; no adverse events were reported. This report highlights a rare dual dermatophyte infection caused by T. soudanense and M. audouinii in Europe, and the successful response to treatment with systemic terbinafine and topical ciclopirox solution as well as clotrimazole cream.

Abstract This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA.

Abstract Dasatinib, a second‐generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH‐sensitive solubility, dasatinib is susceptible to enzyme‐mediated drug–drug interactions (DDIs) with CYP3A4 perpetrators and pH‐dependent DDIs with acid‐reducing agents. This work aimed to develop a whole‐body physiologically‐based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme‐mediated and pH‐dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration–time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%–80% for strong and 0%–70% for moderate CYP3A4 inhibitors and a 2.3–3.1‐fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient‐related factors, such as elevated gastric pH.

Abstract The study aimed to investigate differences in hypertensive‐ and cardio‐preventive pharmacotherapy depending on if patients with hypertension received lifestyle counseling or not, including the difference between men and women. Data from the Region Stockholm VAL database was used to identify all patients with a hypertension diagnosis and had visited a primary health care center within the past five years. Data included registered diagnoses, pharmacotherapy, and codes for lifestyle counseling. Logistic regression adjusted for age and comorbidity (diabetes, stroke, coronary heart disease, atrial fibrillation, gout, obesity, heart failure) was used, presenting results as odds ratios (OR) with 99% confidence interval (CI). The study included 130,030 patients with hypertension; 63,402 men and 66,628 women. Patients receiving recommended lifestyle counseling were more frequently treated with three or more hypertensive drugs: women OR 1.38 (1.31, 1.45) and men = 1.36 (1.30, 1.43); certain drug classes: calcium antagonists: women 1.09 (1.04, 1.14) and men 1.11 (1.06, 1.16); thiazide diuretics: women 1.26 (1.20, 1.34) and men 1.25 (1.19, 1.32); and aldosterone antagonists: women 1.25 (1.12, 1.41) and men 1.49 (1.34, 1.65). Patients receiving recommended level of lifestyle counseling with concomitant coronary heart disease, atrial fibrillation, diabetes, or stroke were more frequently treated with statins than those who did not. Further, recommended lifestyle counseling was significantly associated with anticoagulant treatment in patients with atrial fibrillation. Lifestyle counseling according to recommendations in national guidelines was significantly associated with a more thorough pharmacological treatment of hypertension, statins, and antithrombotic drugs as well as anticoagulants, in both men and women.

Abstract Objectives Migraine is a prevalent neurological disorder severely impacting children and adolescents, yet only one pharmacological treatment is approved for ages 6−12 years. Remote electrical neuromodulation (REN) is a nonpharmacological, prescribed, wearable device cleared by the Food and Drug Administration for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. This study evaluates REN's safety and efficacy in ages 6−11 years. Methods Prospective acute treatment of migraine data were collected through the REN device (Nerivio) smartphone application. Endpoints were device safety (primary); consistent treatment efficacy (headache pain, functional disability, associated migraine symptoms), and REN‐medication combinations 2 h post‐treatment. Results Children (n = 293), median age 11 years (interquartile range = 9−11), 73.7% girls, conducted 5493 REN treatments. No adverse events were reported. Efficacy in at least 50% of REN treatments was calculated from all patients who voluntarily reported pain levels, symptoms, and/or disability at treatment onset and at 2 h post‐treatment, with 72.2% (13/18) of patients reporting pain relief, 36.0% (9/25) pain freedom, 83.3% (15/18) functional disability relief, and 38.9% (7/18) functional disability freedom. Migraine‐associated symptoms disappeared in at least 50% of REN treatments in 70.0% (7/10) of patients for nausea/vomiting, 50.0% (4/8) phonophobia, and 22.2% (2/9) photophobia; 63.6% (7/11) reported freedom from at least one associated symptom. REN was used as a standalone treatment, with over‐the‐counter medications, and with prescribed headache medications in 45.4%, 34.4%, and 20.9% of treatments, respectively. Interpretation REN may serve as a safe and efficacious acute treatment of migraine for children. Providers and families seeking a safe, effective, pill‐ and needle‐free treatment option for children suffering from migraine may consider REN.

Abstract The first‐generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug–drug interactions (DDIs) when co‐administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N‐desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co‐medications. This work presents the development of a parent–metabolite whole‐body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK‐Sim® using a total of 60 plasma concentration–time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P‐glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model‐informed drug development or the support of model‐informed precision dosing.

Abstract Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation.

Ferroptosis is a newly identified iron‐dependent type of regulated cell death that can also be regarded as death caused by the specific collapse of the lipid antioxidant defence machinery. Ferroptosis has gained increasing attention as a potential therapeutic strategy for therapy‐resistant cancer types. However, many ferroptosis‐inducing small molecules do not reach the pharmacokinetic requirements for their effective clinical use yet. Nevertheless, their clinical optimization is under development. In this review, we summarize the current understanding of molecular pathways regulating ferroptosis, how cells protect themselves from the induction of ferroptotic cell death, and how a better understanding of cancer cell metabolism can represent vulnerabilities for ferroptosis‐based therapies. Lastly, we discuss the context‐dependent effect of ferroptosis on various cell types within the tumor microenvironment and address controversies on how tissue ferroptosis might impact systemic cancer immunity in a paracrine manner.

Objective Over 90 clinical trials demonstrate the efficacy of the collaborative care model (CoCM) to treat depression in primary care but there is significant variability in real‐world CoCM implementation and scalability. This study aimed to determine the feasibility and effectiveness of an adapted CoCM in a safety‐net primary care setting. Methods Bring It Up! (BIU) is a pilot trial comparing an adapted CoCM (intervention group) to usual care (historical controls) for primary care safety‐net clinic patients with depression. Inclusion criteria: (1) age ≥18; (2) Patient Health Questionnaire‐9 (PHQ‐9) score ≥10; and (3) major depressive disorder diagnosis. Patients who completed ≥6 months of treatment upon rolling enrollment (April 1, 2018–October 31, 2019) were included. Historical controls completed ≥6 months of usual care in 2017. BIU included all aspects of CoCM except accountable care and leveraged existing staff rather than a dedicated care manager. The primary outcome was depression remission (PHQ‐9

Abstract Background Atopic dermatitis (AD) is characterized by skin barrier dysfunction and immune dysregulation. Autophagy, which is important for the epidermal differentiation, is impaired in AD. The treatment with dupilumab, an interleukin (IL)‐4/IL‐13 receptor blocker, has been shown to reduce skin inflammation and restore the skin barrier. Objectives This study aimed to investigate the effect of dupilumab on the expression of key proteins involved in autophagy and lysosomal degradation. Methods We performed immunofluorescence staining and microscopic analyses of skin specimens of AD patients, taken before and under (6–10 weeks) therapy with dupilumab, to investigate the expression of autophagy‐related (ATG) 5 and ATG7 proteins, beclin‐1, microtubule‐associated protein light chain 3 (LC3B), sequestosome‐1 (p62), lysosomal proteases (cathepsins B, D and L), serine protease inhibitors (SERPINB3, SERPINB4) as well as IL‐33 and thymic stromal lymphopoietin (TSLP). Results The expression of LC3B and p62 as well as SERPINB3 and SERPINB4 was highly increased in untreated AD skin compared to non‐lesional skin and normal skin and decreased upon dupilumab therapy. In contrast, the AD‐associated increased expression of both ATG5 and ATG7 further increased under therapy. Before therapy, cathepsin D and L expression levels were significantly lower compared to normal skin, but increased following the initiation of dupilumab therapy. The increased expression of IL‐33 and TSLP in the epidermis of AD patients correlated with that of LC3B and p62. Conclusions Our study provides further evidence that autophagy is inhibited in lesional AD skin owing to lysosomal dysfunction. Upon dupilumab therapy, a restoration of dysregulated key players of autophagy is observed.

Abstract The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2–7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF‐1 z‐scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. Plain Language Summary The KD can be an effective treatment for difficult‐to‐control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Abstract In the Southern Ocean, phytoplankton blooms are an annually recurring prominent feature that play a significant role in ocean CO2 uptake. Understanding the timing of the phytoplankton bloom is necessary to provide insights into the underlying physiological drivers, for the study of ecosystem dynamics and consequent patterns in downward carbon export. Previous studies have used chlorophyll (chl) and particulate organic carbon, from either satellites or biogeochemical‐Argo (BGC‐Argo) floats, to investigate bloom phenology, but provide inconsistent findings regarding bloom timing. Here, we compare bloom dynamics based on three diagnostics from 7114 BGC‐Argo float profiles, south of 60°S. Bloom onset consistently occurs earlier when calculated using chl than when based on phytoplankton carbon or nitrate uptake, and the decoupling increases with latitude. This suggests that phytoplankton synthesize increased chl to acclimate to low‐light conditions, before increasing their biomass. These results highlight the importance of considering phytoplankton physiology when choosing proxies for phytoplankton growth.

Abstract Objective Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence‐based recommendations for their integration into practice. Methods In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research‐led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. Results Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for

Abstract Objective More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α‐synuclein seed amplification assay (αSyn‐SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co‐pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Methods Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn‐SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Results Following a decade‐long follow‐up, the clinically or autopsy‐defined diagnosis changed for nine participants. αSyn‐SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non‐LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co‐pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p

Abstract Insects are the major pollination vectors for angiosperms, and insects native to a given habitat can play an irreplaceable ecological role in food webs and plant reproduction. With precipitous declines in insect species over the last decades, it is urgent to document insect assemblages in native plant communities to support conservation efforts. Identifying pollinators and their pollination activity is challenging; however, emerging technological methods are providing new monitoring capabilities. In this study, we compare the accuracy of two different methods of monitoring to assess the flower‐visiting insect assemblage and likely pollinators of Encinitas baccharis (Baccharis vanessae): focal observations and video recordings from camera traps. B. vanessae is a rare, endemic species found in Coastal Sage Scrub communities in San Diego County. This federally listed species is threatened by habitat loss and fragmentation, which may also be affecting the availability of its insect pollinators. Results indicate that B. vanessae supports and is supported by a variety of flower‐visiting insect groups. The diversity of insect visitors at male and female plants were similar across all diversity measurements. The insect vectors identified were as expected given B. vanessae pollination syndrome. This syndrome also aligns with wind as a pollination vector, providing evidence of ambophily. While focal observations underreported insect activity by approximately half, the proportions of common diurnal visitors were similar with both methods. Camera traps were unable to provide sufficient detail to discern visually similar groups, but were able to record nocturnal insect activity, which was dominated by moths (Lepidoptera, 82%). While collection protocol in this study did not record the time an insect spent interacting with a flower, we anecdotally observed moths spent notably longer periods in contact with flowers than most diurnal insects. This study has implications for effective monitoring and conservation of endangered plant species and their affiliated pollinators.

ABSTRACT Annuality and perenniality represent two different life‐history strategies in plants, and an analysis of genomic differentiation between closely related species of different life histories bears the potential to identify the underlying targets of selection. Additionally, understanding the interactions between patterns of recombination and signatures of natural selection is a central aim in evolutionary biology, because patterns of recombination shape the evolution of genomes by affecting the efficacy of selection. Here, our aim was to characterise the landscape of genomic differentiation between weedy annual rye (Secale cereale L.) and wild perennial rye (Secale strictum C. Presl), and explore the extent to which signatures of selection are influenced by recombination rate variation. We used population‐level sequence data of annual and perennial rye to analyse population structure and their demographic history. Based on our analyses, annual and perennial rye diverged approximately 26,500 years ago (ya) from an ancestral population size of ~85,000 individuals. We analysed patterns of genetic diversity and genetic differentiation, and found highly differentiated regions located in low‐recombination regions, indicative of linked selection. Although all highly differentiated regions, as revealed by FST‐outlier scans, were located in low‐recombining regions, not all chromosomes showed this tendency. We therefore performed a gene ontology enrichment analysis, which showed that highly differentiated regions comprise genes involved in photosynthesis. This enrichment was confirmed when FST outlier scans were performed separately in low‐ and intermediate‐recombining regions, but not in high‐recombining regions, suggesting that local recombination rate variation in rye affects outlier scans. Cultivated rye is an annual crop, but the introduction of perenniality may be advantageous in regions with poor soil quality or under low‐input farming. Although the resolution of our analysis is limited to a broad‐scale, knowledge about the evolutionary divergence between annual and perennial rye might support breeding efforts towards perennial rye cultivation.

ABSTRACT Aims Increasing attention has been given to the concept resilience in the context of healthcare especially during and post the COVID pandemic. Much of the inquiry and evidence reported has focused on promoting or enhancing resilience in healthcare for improving the quality of care and reducing medical negligence. This discursive paper aims to highlight how resilience is conceptualised and identify any potential limitations or gaps in the context of healthcare students, acknowledging considerations for further development and research into this topic. Design and Methods This discursive discussion draws on relevant theoretical underpinnings from the fields of adjustment and coping psychology, and research and evidence from health sciences, for facilitating an understanding of resilience in supporting healthcare students to adapt into professional practice. Results Investigation of resilience in healthcare students is mainly identified at an individual level as personal traits or skills for working within complex healthcare systems and clinical environments. Less attention has been given to examining resilience at the organisation or systemic level. This is primarily because of limited frameworks for investigating resilience from a multidimensional perspective recognising a wider systemic level influenced by external factors including socioecological determinants, for example, available support services for healthcare students. Conclusions The link between resilience and its function to mitigate against associated neuropsychological distress and subsequent pathopsychological disorders in healthcare student cohorts is recognised; however, greater understanding of resilience as a multidimensional construct is warranted. Relevance to Clinical Practice A multidimensional investigation of resilience is critical for the preparation and readiness of healthcare structures and organisations in facilitating the needs of healthcare students entering challenging and diverse healthcare working environments. Patient or Public Contribution No patient or public contribution.

ABSTRACT Background Apathy is a debilitating behavioral change in Huntington's disease (HD), but impulsivity in HD has not been well documented, and the co‐occurrence of these behaviors in HD has not been investigated. Objective Our objective was to determine whether apathy and impulsivity co‐occur in people with HD and their associations with quality of life. Methods Carriers of Huntington's gene expansion (premanifest to mild motor manifest disease; n = 42) along with healthy controls (n = 20) completed measures of apathy (Apathy Evaluation Scale and Apathy Motivation Index) and impulsivity (Barratt Impulsiveness Scale‐11 and UPPS‐P impulsivity scale), along with mood, cognition, clinical, and quality of life measures. Apathy and impulsivity measures were each reduced to a single metric per patient using principal component analysis. Correlations and multiple linear regression models determined associations between apathy and impulsivity and the potential influence of other covariates. Results Apathy and impulsivity were significantly correlated (r = 0.6, p

Background When more patients with congenital heart disease reach adult age, increased incidence of long‐term complications, including ischemic stroke, are expected. The aim of this study was to analyze cumulative incidence of ischemic stroke, associated factors, and case fatality in adult congenital heart disease. Methods and Results The study is based on Swedish national registers on congenital heart disease and stroke. Patients with congenital heart disease were followed between 2001 and 2018 for first‐ever ischemic stroke events (ischemic stroke due to patent foramen ovale excluded). Factors possibly associated with ischemic stroke were analyzed using Cox regression models. Out of 8914 adult patients with congenital heart disease, 108 suffered ischemic stroke over a mean period of 7.6±4.7 years. The mean age at ischemic stroke was 53.8 years, and the cumulative incidence was 0.15% at 1 year, 0.5% at 5 years, and 1.5% at 10 years. In multivariable analysis, age (hazard ratio [HR], 1.04 [95% CI, 1.03–1.06]), diabetes (HR, 2.9 [95% CI, 1.3–6.4]), ejection fraction