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Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Societal Impact Statement Genebanks contribute to global food security, directly influencing societal well‐being, by providing access to seed or genetic material that is more resilient to pests, diseases, and environmental stresses. The ability to develop crops adapted to changing environmental conditions and with high nutritional value means societies can better cope with the adverse effects of climate change, safeguarding food production and rural livelihoods. Enhancing sustainable crop traits, such as improved water‐use efficiency and nutrient utilization, supports the transition toward more sustainable agricultural practices. New technologically advanced phenotyping tools are required to optimally realize the potential of these genetic resources, to identify plant genetic resources that will best enable us to address current global challenges. Summary Plant genebanks have a crucial role as specialized repositories, preserving diverse plant genetic resources and providing essential access to researchers, breeders, and farmers for developing resilient crops. With over 7 million global accessions, these genebanks significantly contribute to global food security, climate change mitigation, and sustainable agriculture. This opinion paper, inspired by an international workshop in 2022 in Wageningen (Netherlands), focuses on the transformative impact of phenomics technology within genebanks, offering a view on its potential applications and implications for preserving and utilizing plant genetic resources. Discussions from the 2022 workshop organized by the International Plant Phenotyping Network are integrated, emphasizing the potential of phenomics for global collaboration without requiring major policy developments. The workshop prioritized traits like disease resistance and drought tolerance, highlighting roots as a critical organ for phenotyping. Participants expressed a keen interest in global collaboration, emphasizing the need for partnerships between genebanks and advanced phenotyping facilities. The workshop's outcomes underscore the transformative impact of phenomics on genebanks, promoting innovation, collaboration, and sustainable agricultural practices. These results will guide future pilot studies, marking a significant step toward integrating phenomics into genebank practices and ensuring the continued prosperity of plant genetic heritage.

In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell‐to‐cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium‐enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell‐to‐cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM‐mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network. We draw an analogy between the proposed therapeutic outlook and the Alcatraz Federal Penitentiary, where inmates faced an impassable sea barrier and experienced both spatial and functional isolation within individual cells. Based on current translational efforts and ongoing clinical trials, we propose the Alcatraz‐Strategy as a promising framework to tackle the harmful effects of cellular brain tumour networks.

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 Objective Because of its high prognostic value, neuropsychological assessment plays a crucial role in the neuro‐oncology setting. Subjective and objective cognitive performance correlate only to a limited extent, and subjective cognitive performance is strongly dependent on emotional state. We postulate that the relation of subjective and objective cognitive performance depends on tumor laterality. Methods In this prospective study, N = 63 patients with brain tumors underwent a neuropsychological test battery, including assessment of subjective cognitive function (attention, memory, executive), and symptoms of depression and anxiety before surgery. Patients with psychiatric comorbidity or severe neurological conditions were excluded. Results There were no significant differences in subjective and objective cognitive function, symptoms of depression and anxiety between left (N = 37) and right (N = 26) hemisphere tumors. All measures of subjective cognitive function correlated highly significantly with symptoms of depression and anxiety in left hemisphere tumor patients (all r ≥ 0.470). In right hemisphere tumor patients, there was no relation between subjective cognitive function and emotional state. Significant laterality differences for correlations of subjective and objective cognitive function were not found and were not significant within the two groups. Conclusions Even when unbiased by symptoms of anxiety and depression, right hemisphere tumor patients show the same discrepancy in subjective and objective cognitive function as left hemisphere tumor patients. This discrepancy may be based on a different mechanism in right hemisphere tumor patients.

ABSTRACT Introduction Erythropoietic Protoporphyria (EPP) caused skin light sensitivity and liver cirrhosis in a 35‐year‐old patient who subsequently developed liver‐failure. Methods In absence of a human leukocyte antigens (HLA)‐matched‐unrelated donor, the father consented in donating for split liver transplantation (SLT) and allogeneic hematopoietic cell transplantation (HCT). Results After bridging therapy and successful SLT a first paternal HCT resulted in graft failure. For a second haploidentical HCT a different regimen was applied leading to engraftment while protoporphyrin (PP) blood‐levels decreased to normal and skin light sensitivity skin disappeared, leading to complete remission in an immunosuppressive‐free patient. Conclusion Haploidentical transplantation is a feasible treatment approach in EPP‐patients. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

ABSTRACT Background Malignant tumors release growth factors, promoting lymphangiogenesis in primary tumors and draining sentinel lymph nodes, ultimately facilitating lymph node metastasis. As a malignant lymphatic tumor entity, lymphangiosarcomas are characterized by low survival rates and limited treatment options. The transcription factor SOX18 plays a crucial role in both lymphatic endothelial cell differentiation and cancer‐induced lymphangiogenesis. Aims In this in vitro study, we investigated the potential therapeutic effect of a small molecule called Sm4, which inhibits SOX18, on lymphatic endothelial and lymphangiosarcoma cells in vitro. Methods and Results Human dermal lymphatic endothelial cells (HDLECs), lymphangiosarcoma cells (MO‐LAS), and other endothelial cell lines were cultured. We found that Sox18 exhibited high mRNA expression levels in both HDLEC and MO‐LAS. Sm4 treatment decreased the Sox18 expression level at the mRNA and protein levels in both HDLEC and MO‐LAS significantly, a phenomenon confirmed through immunofluorescence images. Additionally, Sm4 treatment suppressed the expression of key lymphatic phenotype markers (Prox1, Flt4, and Lyve1) and hindered migration in both HDLEC and MO‐LAS, all while maintaining cell viability. Conclusion These findings suggest that targeting SOX18 with Sm4 may hold potential as a therapeutic strategy for lymphangiosarcoma and cancer‐induced lymphatic metastasis. Further in vitro studies are warranted to investigate the mechanisms and conduct dose–response analyses to evaluate Sm4's potential as a targeted therapy for lymphangiosarcoma and cancer‐induced lymphangiogenesis in the future.

ABSTRACT Blood flow within the ventricle can provide important information on the performance of the heart. The determined blood flow structures are used to extract flow biomarkers to quantify cardiac function. Patient‐specific computational fluid dynamics (CFD) models that import segmented ventricular deformations from noninvasive imaging data for an individualized hemodynamical analysis are often used. However, tedious preprocessing of those geometries is often necessary and decisions on the modeling of the valve and the surrounding vessels have to be made on an individual level. This leads to a lack of reproducibility and usability of the existing computational models. In this work, we introduce IP‐HEART—an interactive and open‐source computational pipeline to perform geometry processing for CFD models of ventricular blood flow. We showcase its use on real‐time three‐dimensional echocardiography data of three patient datasets from two different clinical centers. We outline how different modeling assumptions of the mitral valve can be implemented and quantify their effect on CFD simulations. The results correspond well with clinical data on transvalvular Doppler ultrasound recordings and distinct flow features such as mitral jet and diastolic vortex formation can be observed. The pipeline is accompanied by an extensive video tutorial and freely available code for further use.

Objective The ADVOCATE trial demonstrated that treatment of active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with avacopan was noninferior in achieving remission at week 26 and superior for sustained remission at week 52 compared with a prednisone taper. This analysis of ADVOCATE evaluated the efficacy and safety of avacopan in patients with ear, nose, throat (ENT), or lung manifestations. Methods This post hoc analysis included patients enrolled in ADVOCATE with ENT or lung manifestations at baseline. Outcomes included remission at weeks 26 and 52, respiratory tract manifestations over time, relapse rate, glucocorticoid‐related toxicity, health‐related quality of life (HRQoL), and safety. Results ADVOCATE included 144 patients with ENT manifestations (avacopan: n = 75, prednisone taper: n = 69) and 142 with lung manifestations (avacopan: n = 71, prednisone taper: n = 71). Among patients with ENT manifestations, remission was achieved at week 26 by 72.0% (avacopan group) and 71.0% (prednisone taper group) and was sustained at week 52 by 62.7% (avacopan) and 53.6% (prednisone taper). Among patients with lung manifestations, remission was achieved at week 26 by 73.2% (avacopan) and 66.2% (prednisone taper) and sustained at week 52 by 67.6% (avacopan) and 53.5% (prednisone taper). The relapse rate, glucocorticoid toxicity, and measures of HRQoL favored avacopan for both respiratory tract manifestation groups. Safety was comparable across treatment groups. Conclusion Patients with GPA or MPA with ENT or lung manifestations demonstrated similar responses to avacopan, reflecting results reported in the overall ADVOCATE trial population and supporting the administration of avacopan in these subgroups.

Abstract Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR‐MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well‐annotated cohort of treatment‐naive patients with LR‐MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome‐wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP‐1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower‐risk IPSS‐M, this cluster displayed a significantly inferior overall survival (p

ABSTRACT This study aimed to evaluate the impact of the myelodysplasia‐related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1‐mutated (NPM1mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1mut AML patients (median age: 59 years) entered into the prospective AMLSG 09‐09 treatment trial. Most commonly co‐mutated genes were DNMT3A (49.8%), FLT3‐TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3‐ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable‐risk NPM1mut AML, multivariable analysis for event‐free survival (EFS) identified age (p

ABSTRACT Aims Atrial fibrillation (AF) accounts for about 20% of all ischemic strokes worldwide. It is known that AF impairs health‐related quality of life (HRQOL) in the general population, but data on HRQOL in stroke patients with newly diagnosed AF are sparse. Methods Post hoc analysis of the prospective, investigator‐initiated, multicenter MonDAFIS study (NCT02204267) to analyze whether AF‐related oral anticoagulation (OAC), and/or AF‐symptom severity are associated with HRQOL after ischemic stroke or transient ischemic attack (TIA). HRQOL was measured using the EQ‐5D‐3L‐questionnaire (including EQ‐index/EQ‐VAS) at baseline and after 12 months using multivariable linear mixed models. AF symptom severity was assessed using the European Heart Rhythm Association classification and symptom severity score (EHRA score) categorizing patients with no/mild/severe/disabling AF‐related symptoms. Results A first episode of AF was detected in 261/2927 (8.9%) patients within 12 months after the index stroke and 227/2920 (7.8%) patients had AF and were anticoagulated at 12 months. HRQOL (measured by EQ‐index, n = 2495 patients) was higher in AF patients on OAC compared to AF patients without OAC at 12 months after stroke (mean difference: MD: –16.8, 95% CI: 5.6 to 28.0), and similar in AF patients under OAC compared with patients without AF (MD: 2.0, 95% CI: –2.2 to 6.3). AF‐related symptoms were negatively associated with HRQOL (measured by EQ‐index) indicating that stroke patients with AF‐related symptoms had a lower HRQOL compared to asymptomatic AF patients (mild vs. asymptomatic: MD: –9.0, 95% CI: –17.7 to –0.3; severe/disabling vs. asymptomatic: MD: –19.1, 95% CI: –34.7 to –3.4). Discussion Stroke patients with newly diagnosed AF are at risk of lower quality of life at 12 months, depending on OAC status and AF symptom severity.

ABSTRACT Purpose: Due to the highly individualized clinical manifestation of Parkinson's disease (PD), personalized patient care may require domain‐specific assessment of neurological disability. Evidence from magnetic resonance imaging (MRI) studies has proposed that heterogenous clinical manifestation corresponds to heterogeneous cortical disease burden, suggesting customized, high‐resolution assessment of cortical pathology as a candidate biomarker for domain‐specific assessment. Method: Herein, we investigate the potential of the recently proposed Mosaic Approach (MAP), a normative framework for quantifying individual cortical disease burden with respect to a population‐representative cohort, in predicting domain‐specific clinical progression. Using MRI and clinical data from 135 recently diagnosed PD patients from the Parkinson's Progression Markers Initiative, we first defined an extremity‐specific motor score. We then identified cortical regions corresponding to “extremity functions” and restricted MAP, respectively, and contrasted the explanatory power of the extremity‐specific MAP to unrestricted MAP. As control conditions, domain‐related but less specific general motor function and nondomain‐specific cognitive scores were considered. We also tested the predictive power of the restricted MAP in predicting disease progression over 1 and 3 years using support vector machines. The restricted, extremity‐specific MAP yielded higher explanatory power for extremity‐specific motor function at baseline as opposed to the unrestricted, whole‐brain MAP. On the contrary, for general motor function, the unrestricted, whole‐brain MAP yielded higher power. Finding: No associations were found for cognitive function. The extremity‐specific MAP predicted extremity‐specific motor progression over 1 and 3 years above chance level. The MAP framework allows for domain‐specific prediction of customized PD disease progression, which can inform machine learning, thereby contributing to personalized PD patient care.

ABSTRACT Global warming changes flowering times of many plant species, with potential impacts on frost damage and their synchronization with pollinator activity. These effects can have severe impacts on plant fitness, yet we know little about how frequently they occur and the extent of damage they cause. We addressed this topic in a thermophilic orchid with a highly specific pollination mechanism, the Small Spider Orchid, Ophrys araneola RchB, in six populations in Northern Switzerland. We measured flowering time, frost damage, and fruiting success in 1250 individually marked plants during 3 years, and documented spring temperatures. Using regression models with historical climate data, we estimated past and future frost damage. In addition, we analyzed historical records of the orchid and its only verified pollinator, the solitary bee Andrena combinata in Northern Switzerland, to estimate potential desynchronization between flowering and pollinator activity due to climate change. Increased spring temperatures accelerated flowering time, and together with the number of frost days explained frost damage well. Frost damage was severe and early‐flowering plants were more likely to be damaged. Historical climate data suggested frost damage has increased in the last decades and may increase further in the future. All populations but one had very low fruit set, and plants that flowered earlier were less likely to set fruit. The historical data from between 1970 and 2019 showed a significant advance of flowering‐ and pollinator occurrence time in the last decades, but to a similar degree in orchids and bees. Our study shows that the orchid, despite being limited to warm habitats in central Europe, suffers under global warming by increased frost damage caused by earlier flowering. We did not detect an effect of accelerated flowering on desynchronization in flowering time and pollinator activity in this orchid species.

Abstract Distinct molecular subtypes of muscle‐invasive bladder cancer (MIBC) may show different platinum sensitivities. Currently available data were mostly generated at transcriptome level and have limited comparability to each other. We aimed to determine the platinum sensitivity of molecular subtypes by using the protein expression‐based Lund Taxonomy. In addition, we assessed the tumor heterogeneity within the primary tumor and between the primary and lymph node (LN) metastatic sites. Thirteen immunohistochemical markers were stained in a tissue microarray with an overall number of 1,508 cores. Statistical evaluation was performed in 199 patients divided into three chemo‐naïve MIBC cohorts: (1) pT3/4 and/or LN+ patients who received radical cystectomy without platinum treatment, (2) patients who received adjuvant chemotherapy (AC), and (3) patients who underwent palliative platinum treatment for metastatic disease or postoperative progression. Overall survival (OS) was used as the primary endpoint. Patients with the genomically unstable (GU) subtype had significantly better OS in the AC group compared to the radical cystectomy group (HR: 0.395, 95% CI: 0.205–0.795, p = 0.005). In contrast, no such association was observed for the basal/squamous (Ba/Sq) subtype. Intratumor heterogeneity was present in 19% of cases, with the lowest level in the Ba/Sq and GU tumors (14% each) and the highest level of 43% in small‐cell/neuroendocrine‐like tumors. There was greater subtype heterogeneity between primary tumors and LN metastases. In conclusion, immunohistochemistry‐based Lund Taxonomy subtypes remain stable within the same primary tumor, with the GU subtype deriving the greatest OS benefit from AC. However, high tumor heterogeneity between the primary tumor and metastatic sites can impact the effectiveness of therapies.

Background Valvular heart disease (VHD) is a major focus of cardiovascular medicine, but limited data are available for racial and ethnic minorities. The aim was to assess the burden and clinical correlates of VHD in a highly diverse area of the United States. Methods and Results Individuals with echocardiographic diagnosis of native VHD between January 2010 and December 2019 at a quaternary care health system of the Bronx (New York, USA) were included. Prevalence and correlates of VHD were assessed per each racial and ethnic group. From a total of 330 570 adult echocardiograms, 80 584 individuals were diagnosed with VHD and included in the final study population. Stratified by race and ethnicity, 38.0%, 23.2%, 2.1%, and 36.7% were non‐Hispanic Black, non‐Hispanic White, Asian, and Hispanic, respectively. The mean age was 67.7±16.3 years, with non‐Hispanic Black, non‐Hispanic Asian, and Hispanic individuals being younger and having a higher burden of comorbidities. The prevalence of VHD increased with age, irrespective of race or ethnicity. In people aged ≥75 years, tricuspid and mitral regurgitation were the most prevalent VHD (21.1% and 16.1%, respectively). Non‐Hispanic White individuals more frequently had tricuspid regurgitation, mitral regurgitation, and multiple VHDs, but among those aged

Background Excessive supraventricular ectopic activity (ESVEA) is regarded as a risk marker for later atrial fibrillation (AF) detection. Methods and Results The investigator‐initiated, prospective, open, multicenter MonDAFIS (Impact of Standardized Monitoring for Detection of Atrial Fibrillation in Ischemic Stroke) study randomized 3465 patients with acute ischemic stroke without known AF 1:1 to usual diagnostic procedures for AF detection or additive Holter monitoring in hospital for up to 7 days, analyzed in a core laboratory. Secondary study objectives include the comparison of recurrent stroke, myocardial infarction, major bleeding, and all‐cause death within 24 months in patients with ESVEA (defined as ectopic supraventricular beats ≥480/day or atrial runs of 10–29 seconds or both) versus patients with newly diagnosed AF versus patients without ESVEA or AF (non‐ESVEA/AF), randomized to the intervention group. Overall, 1435 (84.8%) of 1714 patients randomized to the intervention group had analyzable study ECG monitoring of at least 48 hours' duration within the first 72 hours of monitoring. ESVEA was detected in 363 (25.3%) patients, while AF was first detected in 48 (3.3%) patients. Within 24 months, AF was newly detected in 67 (18.5%) patients with ESVEA versus 60 (5.9%) patients without ESVEA/AF‐ (P

Abstract The functional response describes feeding rates of consumers as a function of resource density. While models for feeding on a single resource species are well studied and supported by a large body of empirical research, consumers feeding on multiple resource species are ubiquitous in nature. However, laboratory experiments designed for parameterizing multi‐species functional responses (MSFR) are extremely rare, mainly due to logistical challenges and the non‐trivial nature of their statistical analysis. Here, we describe how these models can be fitted to empirical data in a Bayesian framework. Specifically, we address the problem of prey depletion during experiments, which can be accounted for through dynamical modelling. In a comprehensive simulation study, we test the effects of experimental design, sample size and noise level on the identifiability of four distinct MSFR models. Additionally, we demonstrate the method's versatility by applying it to a list of empirical datasets. We identify experimental designs for feeding trials that produce the most accurate parameter estimates in two‐ and three‐prey scenarios. Although noise introduces systematic bias in parameter estimates, model selection performs surprisingly well for the four MSFRs, almost always identifying the correct model even for small datasets. This flexible framework allows the simultaneous analysis of feeding experiments from both single‐ and multi‐prey scenarios, either with or without prey depletion. This will help to elucidate mechanisms such as prey selectivity, prey switching and their implications for food web stability and biodiversity. Our approach equips researchers with the appropriate statistical tools to improve the understanding of feeding interactions in complex ecosystems.

Abstract Objectives Ecological momentary interventions (EMI) are digital mobile health interventions administered in an individual's daily life to improve mental health by tailoring intervention components to person and context. Experience sampling via ecological momentary assessments (EMA) furthermore provides dynamic contextual information on an individual's mental health state. We propose a personalized data‐driven generic framework to select and evaluate EMI based on EMA. Methods We analyze EMA/EMI time‐series from 10 individuals, published in a previous study. The EMA consist of multivariate psychological Likert scales. The EMI are mental health trainings presented on a smartphone. We model EMA as linear dynamical systems (DS) and EMI as perturbations. Using concepts from network control theory, we propose and evaluate three personalized data‐driven intervention delivery strategies. Moreover, we study putative change mechanisms in response to interventions. Results We identify promising intervention delivery strategies that outperform empirical strategies in simulation. We pinpoint interventions with a high positive impact on the network, at low energetic costs. Although mechanisms differ between individuals ‐ demanding personalized solutions ‐ the proposed strategies are generic and applicable to various real‐world settings. Conclusions Combined with knowledge from mental health experts, DS and control algorithms may provide powerful data‐driven and personalized intervention delivery and evaluation strategies.

Abstract Background Often after large animal experiments in spinal research, the question arises—histology or biomechanics? While biomechanics are essential for informed decisions on the functionality of the therapy being studied, scientists often choose histological analysis alone. For biomechanical testing, for example, flexibility, specimens must be shipped to institutions with special testing equipment, as spine testers are complex and immobile. The specimens must usually be shipped frozen, and, thus, biological and histological investigations are not possible anymore. To allow both biomechanical and biological investigations with the same specimen and, thus, to reduce the number of required animals, the aim of the study was to develop a spine tester that can be shipped worldwide to test on‐site. Methods The “Spine Tester TO GO” was designed consisting of a frame with three motors that initiate pure moments and rotate the specimen in three motion planes. A load cell and an optical motion tracking system controlled the applied loads and measured range of motion (ROM) and neutral zone (NZ). As a proof of concept, the new machine was validated and compared under real experimental conditions with an existing testing machine already validated employing fresh bovine tail discs CY34 (n = 10). Results The new spine tester measured reasonable ROM and NZ from hysteresis curves, and the ROM of the two testing machines formed a high coefficient of determination R2 = 0.986. However, higher ROM results of the new testing machine might be explained by the lower friction of the air bearings, which allowed more translational motion. Conclusions The spine tester TO GO now opens up new opportunities for on‐site flexibility tests and contributes hereby to the 3R principle by limiting the number of experimental animals needed to obtain full characterization of spine units at the macroscopic, biomechanical, biochemical, and histological level.

Abstract Background and Aim Endoscopic submucosal dissection (ESD) is considered the best modality for achieving en bloc resection of larger neoplastic mucosal lesions in the upper and lower gastrointestinal (GI) tract. Multiple devices are available for ESD, and refinements continue to be made to develop devices that improve the safety and efficiency of performing ESD. Submucosal injection with viscous fluids like glycerol, which prolong submucosal expansion, could facilitate the procedure. We aimed to evaluate the safety and performance of the new Erbe HYBRIDknife® flex, which combines electrosurgical dissection with waterjet‐assisted injection in a slim and flexible form factor. Methods In a prospective animal study with six pigs, four endoscopists, each with 10–20 years of experience in ESD, performed 28 esophageal ESDs. One half was performed with physiological saline injectate, the other half with fructose‐added glycerol. Various performance aspects were evaluated on a five‐point scale [5 = best], including dissection properties, handling, and usability. Results No perforations or major bleeding occurred. All resections were performed en bloc, with one technical failure (3.6%, 1 of 28). Performance scores were similar for saline and glycerol (4.5 ± 0.31 vs. 4.5 ± 0.32, P = 0.36), as was dissection speed (13 ± 6.2 mm2/min vs. 15 ± 6.1 mm2/min, P = 0.22). Conclusions We demonstrated that esophageal ESD can be performed safely and rapidly using HYBRIDknife flex, with excellent performance evaluation by the endoscopists. Combining this device with glycerol or saline is precise and effective for ESD, although experience could compensate for the theoretical disadvantage of using normal saline.

ABSTRACT Background Despite constant improvements, incontinence is one of the most relevant and quality‐of‐life‐reducing side effects of radical prostatectomy (RP) and, in addition to patient‐specific factors such as age, the experience of the surgeon/center and the surgical technique used play an important role. Aims To present current real‐world data on short‐term incontinence after RP from one of the largest German rehabilitation centers in 2022 and to compare it to the results from the same institution in 2016. Methods and Results Retrospective, unicentric, univariate analysis of data from 1394 men after RP in 2022 on admission and discharge from the rehabilitation clinic. Incontinence defined as ≥ 1 pad/day was evaluated by quantitative measuring all day incontinence under a defined graduation and compared to the results of 2016. Totally, 1393 men were available for analysis in 2022 compared to 1390 in 2016. Median age for both cohorts was 66 years with minor differences in preoperative PSA levels. Despite different surgical approaches, no significant change in short‐term incontinence rates in 2016 and 2022 were noted at discharge (76.9% vs. 77.9%, p = 0.56). A notable increase in patients with ISUP grade Group 2 and a shift towards robotic surgery were observed in 2022 (45.5%–71%). While nerve sparing led to a significant improvement in continence (p 69 years exhibited the highest risk of short‐term incontinence and least likelihood of regaining continence during rehabilitation (p

Abstract Both agricultural lands and the role of crop advisors remain comparatively understudied in the Intermountain West (IMW) when it comes to the topic of soil health. Data from a survey of crop advisors in Utah is used to understand current and future soil health work in the region. Not all crop advisors engage in soil health work, but more are discussing it with clients than in the past. Respondents noted that information and costs are key barriers for farmers to managing soil health. Advisors also do not always feel they have the information and answers about soil health practices that farmers need. While crop advisors are one option for promoting producer understanding about soil health in the IMW, work is needed to better prepare them, and farmers will need other options and support to be successful in managing soil health.

Abstract Women with intrahepatic cholestasis of pregnancy (ICP) have hypercholanemia alongside an increased risk of dyslipidemia. We investigated how cholic acid (CA) supplementation in murine pregnancy impacts adipose tissue function. Mice were fed normal or 0.5% CA‐supplemented chow from identification of copulatory plug until gestational day 14 or 15 (n = 10–11/group) and were matched experimentally with nonpregnant mice (n = 7/group). Tissue weights were measured alongside plasma bile acids, glucose, lipids, reactive oxygen metabolites (ROM), and adipokines. Subcutaneous and gonadal adipocyte mRNA expression was evaluated. CA supplementation inhibited pregnancy‐associated adipose tissue expansion and decreased fetal weight. CA diet in pregnancy increased LDL‐cholesterol and reduced HDL‐cholesterol. Pregnancy and CA diet reduced lipid metabolism transcript expression in adipocytes. CA supplementation during pregnancy increased plasma ROM by 1.24‐fold and suppressed inflammatory‐modulating pentraxin‐2/3 and insulin‐like growth factor 1 (IGF‐1) levels by >50% and >80%, respectively. Together, we show that hypercholanemia disturbs pregnancy‐associated adipose tissue expansion and mRNA expression in late gestation concomitant with reduced IGF‐1, altered lipid availability and increased inflammation and oxidation, which could impact fetal growth. This work highlights the need to better understand adipose tissue and redox stress changes in ICP pregnancies and the potential implications for fetal health.

Abstract The analysis of vascular morphology and functionality enables the assessment of disease activity and therapeutic effects in various pathologies. Raster‐scanning optoacoustic mesoscopy (RSOM) is an imaging modality that enables the visualization of superficial vascular networks in vivo. In murine models of colitis, deep vascular networks in the colon wall can be visualized by transrectal absorber guide raster‐scanning optoacoustic mesoscopy (TAG‐RSOM). In order to accelerate the implementation of this technology in translational studies of inflammatory bowel disease, an image‐processing pipeline for TAG‐RSOM data has been developed. Using optoacoustic data from a murine model of chemically‐induced colitis, different image segmentation methods are compared for visualization and quantification of deep vascular patterns in terms of vascular network length and complexity, blood volume, and vessel diameter. The presented image‐processing pipeline for TAG‐RSOM enables label‐free in vivo assessment of changes in the vascular network in murine colitis with broad applications for inflammatory bowel disease research.

ABSTRACT Objective The size of unruptured intracranial aneurysms (UIA) remains the most crucial risk factor for treatment decisions. On the other side, there is a non‐negligible portion of small ruptured IA and large stable UIA. This study aimed to identify the patients' characteristics related to IA size in the context of IA rupture status. Methods A total of 2152 patients, with 1002 being hospitalized for an acute aneurysmal subarachnoid hemorrhage (SAH), were included from our institutional IA database. Different demographic and clinical characteristics of patients and IA were collected. IA size was the study endpoint, assessed as continuous variable in univariate and multivariable linear regression analysis, separately for ruptured (R) IA and UIA. Results The mean IA size was 8.3 and 7.3 mm in the UIA and RIA subpopulations, respectively. Higher age (p = 0.003) and baseline blood urea level (p

ABSTRACT Purpose This study describes oncological outcomes and investigates prognostic factors for patients with gliosarcomas (GSM). Methods Histopathologically confirmed GSM patients who underwent treatment at five European institutions were retrospectively analyzed. Results We analyzed 170 patients with a median clinical follow‐up time of 9.2 months. The majority received surgery (94.1%), postoperative radiotherapy (pRT, 81.8%), and temozolomide (TMZ)‐based postoperative chemotherapy (66.5%). The median overall survival (OS) and progression‐free survival (PFS) were 12.3 and 6.6 months, respectively. In the multivariable Cox regression analysis (MVA), the following factors were significantly associated with OS: age per year (hazard ratio (HR): 1.03, p

ABSTRACT Background Cachexia accounts for about 20% of all cancer‐related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established. Methods We evaluated the association between Fn abundance in pre‐surgical stool samples and onset of cachexia at 6 months post‐surgery in n = 87 patients with stages I–III CRC in the ColoCare Study. Results High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4‐fold increased risk of cachexia onset at 6 months post‐surgery (OR = 4.82, 95% CI = 1.15, 20.10, p = 0.03). Conclusion Our findings suggest that high fecal Fn abundance was associated with an increased risk of cachexia at 6 months post‐surgery in CRC patients. This is the first study to link Fn abundance with cachexia in CRC patients, offering novel insights into biological mechanisms and potential management of cancer cachexia. Due to the small sample size, our results should be interpreted with caution. Future studies with larger sample sizes are needed to validate these findings.

Abstract Pleural empyema is a severe condition associated with high morbidity and mortality. Treatment usually consists of pleural drainage with chest tube or surgery, in combination with antimicrobial treatment. Severe pneumonia can evolve in a necrotizing pneumonia, given a higher susceptibility to the occurrence of bronchopleural fistulas with persistent air leaks. This complicates recovery, and surgery may not always be the optimal treatment. We present a case involving a 17‐year‐old female patient who experienced a post‐operative persistent air leak due to necrotizing pneumonia after video‐assisted thoracic surgery decortication for empyema, which was successfully treated using an endobronchial valve. After 6 months the valve was removed without complications. Follow‐up imaging and lung function revealed a limited area of atelectasis and minimal pleural thickening with normal lung volumes.

Abstract Emerging from the intricate interplay of topology and magnetism, the giant anomalous Hall effect (AHE) is the most known topological property of the recently discovered kagomé ferromagnetic Weyl semimetal Co3Sn2S2 with the magnetic Co atoms arranged on a kagomé lattice. Here it is reported that the AHE in Co3Sn2S2 can be fine‐tuned by an applied magnetic field orientated within ≈2° of the kagomé plane, while beyond this regime, it stays unchanged. Particularly, it can vanish in magnetic fields parallel to the kagomé plane and even decrease in magnetic fields collinear with the spin direction. This tunable AHE can be attributed to local spin switching enabled by the geometrical frustration of the magnetic kagomé lattice, revealing that spins in a kagomé ferromagnet change their switching behavior as the magnetic field approaches the kagomé plane. These results also suggest a versatile way to tune the properties of a kagomé magnet.

Abstract Despite routine detection of coseismic acoustic‐gravity waves (AGWs) in Global Navigation Satellite System (GNSS) total electron content (TEC) observations, models of the earthquake‐atmosphere‐ionosphere dynamics, essential for validating data‐driven studies, remain limited. We present the results of three‐dimensional numerical simulations encompassing the entire coupling from Earth's interior to the ionosphere during the Mw 7.8 2016 Kaikoura earthquake. Incorporating the impact of data/model uncertainties in estimating the ionospheric state, the results show a good agreement between observed and simulated slant TEC (sTEC) signals, assessed through a set of metrics. The signals exhibit intricate waveforms, resulting from the integrated nature of TEC and phase cancellation effects, emphasizing the significance of direct signal comparisons along realistic line‐of‐sight paths. By comparing simulation results initialized with kinematic and dynamic source models, the study demonstrates the quantifiable sensitivity of sTEC to AGW source specifications, pointing to their utility in the analysis of coupled dynamics.

Abstract Dated, geo‐referenced museum specimens are a rich data source for reconstructing species' distribution and abundance patterns. However, museum records are potentially biased towards over‐representation of rare species, and it is unclear whether museum records can be used to estimate relative abundance in the field. We assembled 17 coupled field and museum datasets to quantitatively compare relative abundance estimates with the Dirichlet distribution. Collectively, these datasets comprise 73,039 museum records and 1,405,316 field observations of 2,240 species. Although museum records of rare species overestimated relative abundance by 1‐fold to over 100‐fold (median study = 9.0), the relative abundance of species estimated from museum occurrence records was strongly correlated with relative abundance estimated from standardized field surveys (r2 range of 0.10–0.91, median study = 0.43). These analyses provide a justification for estimating species relative abundance with carefully curated museum occurrence records, which may allow for the detection of temporal or spatial shifts in the rank ordering of common and rare species.

Abstract The analysis of public debt determinants is well documented in the literature. However, previous studies give more focus to the economic determinants neglecting the role played by socio‐political factors. The purpose of this study is to fill that gap observed in the literature by investigating the impact of socio‐political factors on CEMAC countries' public debt accumulation in a bivariate relationship. The paper employs the OLS and GLS as baseline models using panel data covering the period from 1980 to 2021. The study uses as alternative techniques the FE, FE‐IV, and the GMM for robustness checks. The empirical findings highlight the system (both presidential and legislative), corruption, Electoral openness and Competitiveness for legislative election (Liec), and fraud as the main driving factors of public debt in CEMAC countries. This paper suggests further studies to give a particular interest to socio‐political factors while investigating the determinants of public debt in developing countries.

Abstract Although epilepsy surgery is the only curative therapeutic approach for lesional drug‐resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta‐analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow‐up of 1.5 years (IQR: 1.8), 57% of patients were seizure‐free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti‐seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Abstract Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato‐oncology products (OP) and non‐oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not‐statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies.

Abstract The case of a 71‐year‐old male with end stage heart failure and severe mitral regurgitation is presented, where percutaneous indirect mitral annuloplasty was performed. During device implantation in the coronary sinus the circumflex artery was compromised at two anatomic locations, while the mitral regurgitation was efficiently reduced. After weighing risks and alternative therapeutic options, stent implantation was chosen as bailout strategy to leave the device in place and retain the efficient MR reduction. The anatomical proximity of Cx and coronary sinus in the mitral valve plane bears the risk of circumflex artery damage during surgical and interventional mitral repair. Usually, a device exchange solves the problem of arterial flow limitation in most cases. While stent implantation remains off label use in this setting and should not be performed without critical evaluation, it has been performed successfully in similar clinical settings as well (e.g. artery stenosis by surgical suture).

Abstract Objective Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post‐treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Methods Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. Results The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Interpretation Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.

Abstract Aim To explore healthcare team members' perceptions of their ethical obligations toward HIV‐positive adolescents and their enrolment in and adherence to antiretroviral therapy among adolescents attending a Care and Treatment Center (CTC) in Temeke Regional Referral Hospital in Tanzania. Design This is a descriptive exploratory qualitative study. Methods A total of 16 healthcare team members were purposively selected from the hospital CTC to participate in in‐depth qualitative interviews. With the aid of NVivo software, qualitative thematic analysis was used to analyze the information. Results Five themes on ethical obligations emerged: (1) informing adolescents of their status before enrolment to the HIV CTC, (2) securing adolescents’ confidential information, (3) disclosing adolescents' HIV status, (4) informing others about the adolescent’s HIV status; and (5) offering reproductive health education for adolescents living with HIV. Conclusion The healthcare team faces many ethical challenges in the care and support of adolescents who enroll in an HIV CTC in Tanzania. Differing ethical obligations must be balanced with the needs of adolescents and their parents in discerning what is in the best interest of the adolescent and advocating for life‐saving treatment.

Abstract Percutaneous and surgical therapies for septal reduction for hypertrophic cardiomyopathy have been going head‐to‐head for the past 20 years with similar outcomes and mortality rates, although contemporary myectomy seems to materialize its superiority. However, on closer analysis, the external validity of studies advocating myectomy does not translate to all centres. The aim of this review was to examine the most recent data on septal reduction therapy and to attempt to phenotype the appropriate patient for each of the two treatments. The key to similar low mortality rates between ventricular septal myectomy and alcohol septal ablation appears to be proper patient selection performed in high volume clinical environments. Furthermore, we analyse the role of mavacampten (the recently approved cardiac myosin inhibitor) in replacing or complementing the two septal reduction therapies.

The use of mutation analysis of homologous recombination repair (HRR) genes to estimate PARP‐inhibition response may miss a larger proportion of responding patients. Here, we provide preclinical models for castration‐resistant prostate cancer (CRPC) that can be used to functionally predict HRR defects. In vitro, CRPC LNCaP sublines revealed an HRR defect and enhanced sensitivity to olaparib and cisplatin due to impaired RAD51 expression and recruitment. Ex vivo‐induced castration‐resistant tumor slice cultures or tumor slice cultures derived directly from CRPC patients showed increased olaparib‐ or cisplatin‐associated enhancement of residual radiation‐induced γH2AX/53BP1 foci. We established patient‐derived tumor organoids (PDOs) from CRPC patients. These PDOs are morphologically similar to their primary tumors and genetically clustered with prostate cancer but not with normal prostate or other tumor entities. Using these PDOs, we functionally confirmed the enhanced sensitivity of CRPC patients to olaparib and cisplatin. Moreover, olaparib but not cisplatin significantly decreased the migration rate in CRPC cells. Collectively, we present robust patient‐derived preclinical models for CRPC that recapitulate the features of their primary tumors and enable individualized drug screening, allowing translation of treatment sensitivities into tailored clinical therapy recommendations.

Abstract A better understanding of the genetic regulation of the biosynthesis of microbial compounds could accelerate the discovery of new biologically active molecules and facilitate their production. To this end, we have investigated the time course of genome‐wide transcription in the myxobacterium Sorangium sp. So ce836 in relation to its production of natural compounds. Time‐resolved RNA sequencing revealed that core biosynthesis genes from 48 biosynthetic gene clusters (BGCs; 92% of all BGCs encoded in the genome) were actively transcribed at specific time points in a batch culture. The majority (80%) of polyketide synthase and non‐ribosomal peptide synthetase genes displayed distinct peaks of transcription during exponential bacterial growth. Strikingly, these bursts in BGC transcriptional activity were associated with surges in the net production rates of known natural compounds, indicating that their biosynthesis was critically regulated at the transcriptional level. In contrast, BGC read counts from single time points had limited predictive value about biosynthetic activity, since transcription levels varied >100‐fold among BGCs with detected natural products. Taken together, our time‐course data provide unique insights into the dynamics of natural compound biosynthesis and its regulation in a wild‐type myxobacterium, challenging the commonly cited notion of preferential BGC expression under nutrient‐limited conditions. The close association observed between BGC transcription and compound production warrants additional efforts to develop genetic engineering tools for boosting compound yields from myxobacterial producer strains.

Abstract Objective Tracheoesophageal fistulas (TEF) following laryngectomy cause immense restrictions due to the inability of oral feeding, loss of voice rehabilitation, penetration of saliva, and permanent need of inflatable tracheal cannulas. Patients are consistently in threat of fatal aspiration pneumonias. The failure rate of surgical approaches to close the fistulas is high and an ultima ratio option by customized silicone prostheses can be considered. Methods A retrospective analysis of 26 patients with a TEF was performed. Results The fistulas occurred in average 40 months after laryngectomy caused by an enlargement of the voice fistula in 17 patients and problems in wound healing in 6 patients. The mean diameter of the fistula was 32 × 18 mm. Eight patients were treated by a button‐shaped and 18 by a tube‐shaped prosthesis. Complete oral feeding was possible in 8 and additional feeding by percutaneous endoscopic gastrostomy tube in 16 patients. Voice rehabilitation by voice prostheses was possible in 18 cases. Fifteen patients died in the course of the treatment either due to oncological progression or other reasons. The median follow‐up time of the patients alive was 36 months (max 88 months) with 2.2 protheses replacements in mean (max 11). Conclusion The treatment of TEF by customized prostheses can be considered as an ultima ration option if other approaches had failed. At least, partial oral nutrition and voice rehabilitation as well as protection from aspiration can be achieved in the majority of the patients. Level of Evidence 4—Case series.

Abstract Intrahepatic cholangiocarcinoma harbours druggable genetic lesions including FGFR2 gene fusions. Reliable and accurate detection of these fusions is becoming a critical component of the molecular work‐up, but real‐world data on the performance of fluorescence in situ hybridisation (FISH) and targeted RNA‐based next‐generation sequencing (NGS) are very limited. Bridging this gap, we report results of the first round robin test for FGFR2 fusions in cholangiocarcinoma and contextualise test data with genomic architecture. A cohort of 10 cholangiocarcinoma (4 fusion positive and 6 fusion negative) was tested by the Institute of Pathology, University Hospital Heidelberg, Germany. Data were validated by four academic pathology departments in Germany. Fusion‐positive cases comprised FGFR2::BICC1, FGFR2::DBP, FGFR2::TRIM8, and FGFR2::ATE1 fusions. In a second step, a round robin test involving 21 academic and non‐academic centres testing with RNA‐based NGS approaches was carried out; five participants performed FISH testing in addition. Thirteen of 16 (81%) centres successfully passed the NGS only and 3 of 5 (60%) centres passed the combined NGS + FISH round robin test. Identified obstacles were bioinformatic pipelines not optimised for the detection of FGFR2 fusions and assays not capable of detecting unknown fusion partners. This study shows the benefit of targeted RNA‐NGS for the detection of FGFR2 gene fusions. Due to the marked heterogeneity of the genomic architecture of these fusions, fusion partner agnostic (i.e. open) methodological approaches that are capable of identifying yet unknown fusion partners are superior. Furthermore, we highlight pitfalls in subsequent bioinformatic analysis and limitations of FISH‐based tests.

Abstract Objective Although targeted approaches have become available in second‐ and third‐line settings, platinum‐based chemotherapy remains the standard first‐line treatment for advanced muscle‐invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance. Methods In this study, we established a routine compatible method for the molecular classification of MIBC samples according to various classification systems and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy. This retrospective study included 191 patients with advanced MIBC (pT≥3 or pN+) who underwent radical cystectomy, with or without adjuvant chemotherapy. A 48‐gene panel and classifier rule set were established to determine molecular subtypes according to TCGA, MDA, LundTax, and Consensus classifications. Additionally, 12 single platinum‐predictive candidate genes were assessed. The results were correlated with patients' clinicopathological and follow‐up data and were validated using independent data sets. Results Our final evaluation of 159 patients demonstrated better survival in the luminal groups for those who received chemotherapy compared with those who did not. In contrast, no such differences were observed in basal subtypes. The use of chemotherapy was associated with better survival in patients with high APOBEC3G expression (p

Abstract Aims Maintaining quality of life (QoL) in patients with cancer has gathered significant interest, but little is known about its major determinants. We sought to identify determinants of QoL in patients undergoing cancer treatment as well as in treatment‐naïve patients about to commence such therapy. Methods and results QoL was assessed in 283 patients with cancer using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. All patients underwent a battery of tests including physical examination, resting electrocardiogram, hand grip strength, and biochemistry assessment. Using multivariable logistic regression, we found that age [odds ratio (OR) 0.954, 95% confidence interval (CI) 0.916–0.994], resting heart rate (OR 1.036, 95% CI 1.004–1.068), hand grip strength (OR 0.932, 95% CI 0.878–0.990), and the presence of cachexia (OR 4.334, 95% CI 1.767–10.631) and dyspnoea (OR 3.725, 95% CI 1.540–9.010; all P

Abstract Aims Therapeutic options targeting post‐ischaemic cardiac remodelling are sparse. The bioactive sphingolipid sphingosine‐1‐phosphate (S1P) reduces ischaemia/reperfusion injury. However, its impact on post‐ischaemic remodelling independently of its infarct size (IS)‐reducing effect is yet unknown and was addressed in this study. Methods and results Acute myocardial infarction (AMI) in mice was induced by permanent ligation of the left anterior descending artery (LAD). C57Bl6 were treated with the S1P lyase inhibitor 4‐deoxypyridoxine (DOP) starting 7 days prior to AMI to increase endogenous S1P concentrations. Cardiac function and myocardial healing were assessed by cardiovascular magnetic resonance imaging (cMRI), murine echocardiography, histomorphology, and gene expression analysis. DOP effects were investigated in cardiomyocyte‐specific S1P receptor 1 deficient (S1PR1 Cardio Cre+) and Cre− control mice and S1P concentrations measured by LC‐MS/MS. IS and cardiac function did not differ between control and DOP‐treated groups on day one after LAD‐ligation despite fourfold increase in plasma S1P. In contrast, cardiac function was clearly improved and myocardial scar size reduced, respectively, on Day 21 in DOP‐treated mice. The latter also exhibited smaller cardiomyocyte size and reduced embryonic gene expression. The benefit of DOP treatment was abolished in S1PR1 Cardio Cre+. Conclusions S1P improves cardiac function and myocardial healing post AMI independently of initial infarct size and accomplishes this via the cardiomyocyte S1PR1. Hence, in addition to its beneficial effects on I/R injury, S1PR1 may be a promising target in post‐infarction myocardial remodelling as adjunctive therapy to revascularization as well as in patients not eligible for standard interventional procedures.

Abstract Ample evidence suggests positive effects of species diversity on ecosystem functioning and services in natural and agricultural landscapes. Less obvious and even contested are the effects of such diversity on human well‐being. This state of art partly stems from methodological difficulties to evaluate and quantify these effects and imprecise conceptual frameworks. Here we propose a conceptual framework that links different aspects of diversity, particularly species and genetic richness, to ecosystem functioning, ecosystem services and disservices, and different aspects of well‐being. We review current approaches for the study of diversity–well‐being relationships and identify shortcomings and principle obstacles, mainly stemming from theoretical premises that are too imprecise. We discuss five basic methodological approaches to link diversity to well‐being: matrix models, indirect inference, Price partitioning, structural equation modelling, and environmental inference. We call for a stricter terminology with respect to the different aspects of functioning, multifunctionality and well‐being and highlight the need to evaluate each step in the different pathways from diversity to well‐being. A full understanding of ecological constraints on human well‐being requires consideration of trade‐offs in diversity effects, of contrasting perceptions of well‐being, and of ecosystem disservices. We also call for appropriate long‐term socio‐ecological research platforms to gather relevant data about ecosystem functioning and well‐being across space and time. Read the free Plain Language Summary for this article on the Journal blog.