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IMPORTANCE: Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. OBJECTIVE: To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus–specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. EXPOSURE: Fresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. MAIN OUTCOMES AND MEASURES: Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. RESULTS: The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). CONCLUSION AND RELEVANCE: This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

Background: Prior investigations have elucidated pathophysiological interactions involving blood coagulation and neurodegenerative diseases. These interactions pertain to age-related effects and a mild platelet antiaggregant function of exogenous α-Synuclein.Objective: Our study sought to explore whether cerebrospinal fluid (CSF) levels of tissue factor (TF), the initiator of the extrinsic pathway of hemostasis, differ between controls (CON) compared to patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), considering that these conditions represent a spectrum of α-Synuclein pathology. We further investigated whether TF levels are associated with longitudinal progression in PD.Methods: We examined CSF levels of TF in 479 PD patients, 67 patients diagnosed with DLB, and 16 CON in order to evaluate potential continuum patterns among DLB, PD, and CON. Of the 479 PD patients, 96 carried a GBA1variant (PD GBA1), while the 383 non-carriers were classified as PD wildtype (PD WT). We considered both longitudinal clinical data as well as CSF measurements of common neurodegenerative markers (amyloid-β 1-42, h-Tau, p-Tau, NfL, α-Synuclein). Kaplan-Meier survival and Cox regression analysis stratified by TF tertile levels was conducted.Results: Higher CSF levels of TF were associated with an older age at examination in PD and a significant later onset of postural instability in PD GBA1. TF levels were lower in male vs. female PD. DLB GBA1exhibited the lowest TF levels, followed by PD GBA1, with CON showing the highest levels.Conclusions: TF as representative of blood hemostasis could be an interesting CSF candidate to further explore in PD and DLB.

Prior investigations have elucidated pathophysiological interactions involving blood coagulation and neurodegenerative diseases. These interactions pertain to age-related effects and a mild platelet antiaggregant function of exogenous α-Synuclein. Our study sought to explore whether cerebrospinal fluid (CSF) levels of tissue factor (TF), the initiator of the extrinsic pathway of hemostasis, differ between controls (CON) compared to patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), considering that these conditions represent a spectrum of α-Synuclein pathology. We further investigated whether TF levels are associated with longitudinal progression in PD. We examined CSF levels of TF in 479 PD patients, 67 patients diagnosed with DLB, and 16 CON in order to evaluate potential continuum patterns among DLB, PD, and CON. Of the 479 PD patients, 96 carried a GBA1variant (PD GBA1), while the 383 non-carriers were classified as PD wildtype (PD WT). We considered both longitudinal clinical data as well as CSF measurements of common neurodegenerative markers (amyloid-β 1-42, h-Tau, p-Tau, NfL, α-Synuclein). Kaplan-Meier survival and Cox regression analysis stratified by TF tertile levels was conducted. Higher CSF levels of TF were associated with an older age at examination in PD and a significant later onset of postural instability in PD GBA1. TF levels were lower in male vs. female PD. DLB GBA1exhibited the lowest TF levels, followed by PD GBA1, with CON showing the highest levels. TF as representative of blood hemostasis could be an interesting CSF candidate to further explore in PD and DLB. Parkinson’s disease is a common age-related condition, primarily affecting older individuals. However, it shows a wide range of symptoms and clinical courses, influenced by genetic mutations, neuroinflammatory processes and lifestyle factors. Research into the disease’s mechanisms is important for developing new therapies that could potentially slow its progression. Early diagnosis is also essential, as new disease-modifying therapies are most effective when started at an early stage of the disease. In this paper, we focus on a protein called tissue factor, which plays a role in both blood coagulation and neuroinflammation. Proteins involved in blood-coagulation also exhibit an increase in blood-concentration with higher age. Also, a subtle platelet antiaggregant function of exogenous α-Synuclein was found, a protein which aggregates in the brain of patients with Parkinson’s disease. Additionally, higher tissue factor levels were found in plaques of proteins (amyloid-β 1-42) found in Alzheimer’s disease. Thus, tissue factor could be a promising biomarker candidate for neurodegenerative diseases. We analyzed the concentration of this protein in the cerebrospinal fluid of 479 patients with Parkinson’s disease, 16 control participants, and 67 patients with dementia with Lewy bodies, a sub-type of Parkinson’s disease with exceptionally high levels of α-Synuclein in the brain. Our findings showed the lowest levels of tissue factor in patients with dementia with Lewy bodies, followed by those with typical Parkinson’s disease, and the highest levels in controls. Additionally, older patients had higher tissue factor levels than younger patients, and levels were lower in male patients compared to female patients. Thus, measuring tissue factor levels could help in diagnosing Parkinson’s disease. Further studies, especially with larger control groups, are needed to confirm these results. Additionally, exploring the connections between blood coagulation and Parkinson’s disease could improve our understanding of the disease’s mechanisms, potentially leading to new pharmaceutical developments.

Auch weil bislang wenig didaktisches Material zum konfessionell-kooperativen Religionsunterricht vorliegt, kommt es zur Einschätzung dessen Praxis gegenwärtig vor allem darauf an, wie die Lehrpersonen konfessionssensible Lerngelegenheiten arrangieren, wie und ob sie die Schüler:innen zu einer differenzsensiblen Auseinandersetzung stimulieren und was diese im kokoRU lernen. Deshalb werden im vorliegenden Beitrag diesbezüglich die Datenlage zur Praxis im kokoRU bilanziert, einschlägige Einsichten aus der Literatur beschrieben und anschließend Implikationen für die Unterrichtspraxis abgeleitet. Dabei sollte bedacht werden, dass zwar vielfältige empirische Indizien zur Praxis des kokoRU vorliegen, diese jedoch durchgehend auf regional fokussierten Gelegenheitsstichproben beruhen und sich auf einen Zeitraum von 20 Jahren verteilen.

Human motion copy is an intriguing yet challenging task in artificial intelligence and computer vision, which strives to generate a fake video of a target person performing the motion of a source person. The problem is inherently challenging due to the subtle human-body texture details to be generated and the temporal consistency to be considered. Existing approaches typically adopt a conventional GAN with an L1 or L2 loss to produce the target fake video, which intrinsically necessitates a large number of training samples that are challenging to acquire. Meanwhile, current methods still have difficulties in attaining realistic image details and temporal consistency, which unfortunately can be easily perceived by human observers. Motivated by this, we try to tackle the issues from three aspects. (1) We constrain pose-to-appearance generation with a perceptual loss and a theoretically motivated Gromov-Wasserstein loss to bridge the gap between pose and appearance. (2) We present an episodic memory module in the pose-to-appearance generation to propel continuous learning that helps the model learn from its past poor generations. We also utilize geometrical cues of the face to optimize facial details and refine each key body part with a dedicated local GAN. (3) We advocate generating the foreground in a sequence-to-sequence manner rather than a single-frame manner, explicitly enforcing temporal inconsistency. Empirical results on five datasets, iPER, ComplexMotion, SoloDance, Fish, and Mouse datasets, demonstrate that our method is capable of generating realistic target videos while precisely copying motion from a source video. Our method significantly outperforms state-of-the-art approaches and gains 7.2% and 12.4% improvements in PSNR and FID respectively.

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA‐acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.

Sensors are the key to environmental monitoring, which impart benefits to smart cities in many aspects, such as providing real-time air quality information to assist human decision-making. However, it is impractical to deploy massive sensors due to the expensive costs, resulting in sparse data collection. Therefore, how to get fine-grained data measurement has long been a pressing issue. In this article, we aim to infer values at nonsensor locations based on observations from available sensors (termed spatiotemporal inference), where capturing spatiotemporal relationships among the data plays a critical role. Our investigations reveal two significant insights that have not been explored by previous works. First, data exhibit distinct patterns at both long- and short-term temporal scales, which should be analyzed separately. Second, short-term patterns contain more delicate relations, including those across spatial and temporal dimensions simultaneously, while long-term patterns involve high-level temporal trends. Based on these observations, we propose to decouple the modeling of short- and long-term patterns. Specifically, we introduce a joint spatiotemporal graph attention network to learn the relations across space and time for short-term patterns. Furthermore, we propose a graph recurrent network with a time skip strategy to alleviate the gradient vanishing problem and model the long-term dependencies. Experimental results on four public real-world datasets demonstrate that our method effectively captures both long- and short-term relations, achieving state-of-the-art performance against existing methods.

With the popularity of GPS-equipped smart devices, spatial crowdsourcing (SC) techniques have attracted growing attention in both academia and industry. A fundamental problem in SC is assigning location-based tasks to workers under spatial-temporal constraints. In many real-life applications, workers choose tasks on the basis of their preferred trajectories. However, by existing trajectory-aware task assignment approaches, tasks assigned to a worker may be far apart from each other, resulting in a higher detour cost as the worker needs to deviate from the original trajectory more often than necessary. Motivated by the above observations, we investigate a trajectory-aware task coalition assignment (TCA) problem and prove it to be NP-hard. The goal is to maximize the number of assigned tasks by assigning task coalitions to workers based on their preferred trajectories. For tackling the TCA problem, we develop a batch-based three-stage framework consisting of task grouping, planning, and assignment. First, we design greedy and spanning grouping approaches to generate task coalitions. Second, to gain candidate task coalitions for each worker efficiently, we design task-based and trajectory-based pruning strategies to reduce the search space. Furthermore, a 2-approximate algorithm, termed MST-Euler, is proposed to obtain a route among each worker and task coalition with a minimal detour cost. Third, the MST-Euler Greedy (MEG) algorithm is presented to compute an assignment that results in the maximal number of tasks assigned and a parallel strategy is introduced to boost its efficiency. Extensive experiments on real and synthetic datasets demonstrate the effectiveness and efficiency of the proposed algorithms.

The Mott insulator Ca2RuO4exhibits an insulator-to-metal transition induced by d.c. current. Despite the thorough examination of the structural changes associated with this transition, a comprehensive knowledge of the response of electronic degrees of freedom is still lacking. Here we demonstrate current-induced modifications of the electronic states of Ca2RuO4. Angle-resolved photoemission spectroscopy in conjunction with four-probe electrical transport (transport-ARPES) measurements reveal a clear reduction of the Mott gap and a modification in the dispersion of the Ru bands. Based on a free-energy analysis, we show that the current-induced phase is electronically distinct from the high-temperature zero-current metallic phase. Our results highlight strong interplay of lattice- and orbital-dependent electronic responses in the current-driven insulator-to-metal transition.

Famously found written on the blackboard of physicist Richard Feynman after his death was the phrase, “What I cannot create, I do not understand.” From this perspective, recreating the origin of life in the lab is a necessary condition for achieving a deep theoretical understanding of biology. The “metabolism-first” hypothesis is one of the leading frameworks for the origin of life. A complex self-organized reaction network is thought to have been driven into existence as a chemical path of least resistance to release free energy in the environment that could otherwise not be dissipated, rerouting energy from planetary processes to organic chemistry. To increase in complexity, the reaction network, initially under catalysis provided by its geochemical environment, must have produced organic catalysts that pruned the existing flux through the network or expanded it in new directions. This boot-strapping process would gradually lessen the dependence on the initial catalytic environment and allow the reaction network to persist using catalysts of its own making. Eventually, this process leads to the seemingly inseparable interdependence at the heart of biology between catalysts (coenzymes, enzymes, genes) and the metabolic pathways that synthesize them. Experimentally, the primary challenge is to recreate the conditions where such a network emerged. However, the near infinite number of microenvironments and sources of energy available on the early Earth or elsewhere poses an enormous combinatorial challenge. To constrain the search, our lab has been surveying conditions where the reactions making up the core of some of the most ancient chemolithoautotrophic metabolisms, which consist of only a small number of repeating chemical mechanisms, occur nonenzymatically. To give a fresh viewpoint in the first part of this account, we have organized the results of our search (along with important results from other laboratories) by reaction mechanism, rather than by pathway. We expect that identifying a common set of conditions for each type of reaction mechanism will help pinpoint the conditions for the emergence of a self-organized reaction network resembling core metabolism. Many of the reaction mechanisms were found to occur in a wide variety of nonenzymatic conditions. Others, such as carboxylate phosphorylation and C–C bond formation from CO2, were found to be the most constraining, and thus help narrow the scope of environments where a reaction network could emerge. In the second part of this account, we highlight examples where small molecules produced by metabolism, known as coenzymes, mediate nonenzymatic chemistry of the type needed for the coenzyme’s own synthesis or that turn on new reactivity of interest for expanding a hypothetical protometabolic network. These examples often feature cooperativity between small organic coenzymes and metal ions, recapitulating the transition from inorganic to organic catalysis during the origin of life. Overall, the most interesting conditions are those containing a reducing potential equivalent to H2gas (electrochemical or H2itself), Fe in both reduced and more oxidized forms (possibly with other metals like Ni) and localized strong electric fields. Environments that satisfy these criteria simultaneously will be of prime interest for reconstructing a metabolic origin of life.

•Cerebral organoids mimic critical structures of the human CNS tissue and can be using to investigate CNS leukemia.•Using cerebral organoids concomitant to PDX mouse models, we identify the AP-1 pathway as a critical driver of CNS leukemia.

Abstract: Neonatology is a pediatric sub-discipline focused on providing care for newborn infants, including healthy newborns, those born prematurely, and those who present with illnesses or malformations requiring medical care. The European Training Requirements (ETR) in Neonatology provide a framework for standardized quality and recognition of equality of training throughout Europe. The latest ETR version was approved by the Union of European Medical Specialists (UEMS) in April 2021. Here, we present the curriculum of the European School of Neonatology Master of Advanced Studies (ESN MAS), which is based on the ETR in Neonatology and aims to provide a model for effective and standardized training and education in neonatal medicine. We review the history and theory that form the foundation of contemporary medical education and training, provide a literature review on best practices for medical training, pediatric training, and neonatology training specifically, including educational frameworks and evidence-based systems of evaluation. The ESN MAS Curriculum is then evaluated in light of these best practices to define its role in meeting the need for a standardized empirically supported neonatology training curriculum for physicians, and in the future for nurses, to improve the quality of neonatal care for all infants. Impact statement:

A review of the neonatology training literature was conducted, which concluded that there is a need for standardized neonatology training across international contexts to keep pace with growth in the field and rapidly advancing technology. This article presents the European School of Neonatology Master of Advanced Studies in Neonatology, which is intended to provide a standardized training curriculum for pediatricians and nurses seeking sub-specialization in neonatology. The curriculum is evaluated in light of best practices in medical education, neonatology training, and adult learning theory.

Colorectal surgery still experiences high rates of infectious complications, such as anastomotic leakage (AL) and surgical site infections (SSIs). Therefore, oral antibiotic bowel decontamination (OABD) has experienced a renaissance. However, data on perioperative selective digestive tract decontamination (SDD)–based regimens or combined bowel preparation are inconsistent. Nonetheless, with widespread use of Enhanced Recovery After Surgery concepts, the ideal length for perioperative SDD treatment has to be reconsidered.

This research investigates the relation between climate anxiety, threat perceptions for future generations, and childbearing motivations in childless emerging adults. Using a sample of 1211 Swiss college students aged 18–25, the study explores if threat perceptions mediate the relationship between climate anxiety and childbearing motivations. Results from structural equation modeling (SEM) indicated that climate anxiety significantly predicted greater perceptions of threat, which in turn related to less positive childbearing motivations and more negative childbearing motivations. Specifically, the relationship between climate anxiety and childbearing motivations was partly to fully explained by threat perceptions, suggesting that worries about the future environment could be an important factor in emerging adults’ complex reproductive considerations. No gender moderation was found. These findings underscore the need for policy interventions that provide psychological support and targeted educational resources to assist young adults in navigating the complex interplay between climate anxiety, threat perceptions, and their decisions regarding childbearing.

Reducing human-made greenhouse gas emissions is crucially important for life on earth, but it requires restructuring industries in ways that could disrupt millions of workers’ lives globally. Whether this transition is “just” from the perspective of workers depends on the magnitude of job losses, the quality of new jobs, and the transitions workers experience from their current jobs to new ones. Using the example of the German automotive industry, where the shift to electric vehicle production has recently accelerated, the authors identify recommendations for unions and policymakers in North America and beyond. This article provides an overview of the tools for workers and trade unions in Germany to steer the transition and shows how analogous tools could be strengthened or created elsewhere.

The analysis of histopathology images with artificial intelligence aims to enable clinical decision support systems and precision medicine. The success of such applications depends on the ability to model the diverse patterns observed in pathology images. To this end, we present Virchow, the largest foundation model for computational pathology to date. In addition to the evaluation of biomarker prediction and cell identification, we demonstrate that a large foundation model enables pan-cancer detection, achieving 0.95 specimen-level area under the (receiver operating characteristic) curve across nine common and seven rare cancers. Furthermore, we show that with less training data, the pan-cancer detector built on Virchow can achieve similar performance to tissue-specific clinical-grade models in production and outperform them on some rare variants of cancer. Virchow’s performance gains highlight the value of a foundation model and open possibilities for many high-impact applications with limited amounts of labeled training data.

Previous studies showed that pre- and probiotics may enhance iron absorption. Probiotics combined with prebiotics (synbiotics), including human-identical milk oligosaccharides (HiMOs), are commonly added to infant and follow-up formula (FUF). Whether these additions enhance iron absorption from iron-fortified commercial milk formula is uncertain.

Graphical abstract:

•This study reveals a novel recurrent genetic variant (TRB::NOTCH1) with significant prognostic relevance in T-LBL.•TRB::NOTCH1is absent in the analyzed T-ALL cohort.

In the industrial sector, products evolve significantly over their operational life. A key challenge has been maintaining precise, relevant engineering data. This paper explores the digital twin concept, merging engineering and operational data to enhance product information updates. It examines digital twin applications in construction, material flow, manufacturing and production, citing battery production and additive manufacturing. Digital twins aid in analyzing, experimenting with, and refining a system’s design and its operation, offering insights across product and system lifecycles. This includes tackling data management and model-data consistency challenges, as well as the recognition of synergies. This paper emphasizes sustainable, efficient management of engineering information, reflecting shifts in product longevity and documentation in industrial products and machinery.

Besides safety and security applications, ion mobility spectrometry (IMS) is increasingly used in other fields such as medicine, environmental monitoring and food quality analysis. However, some applications require gas chromatographic separation before analysis by IMS. Furthermore, different compounds in the sample may form positive or negative ions during ionization and therefore simultaneous detection of both ion polarities is highly beneficial to avoid two chromatographic runs of the same sample. This can be achieved by ultra-fast polarity switching of a single drift tube IMS, allowing for quasi-simultaneous detection of both ion polarities. By using a ramped aperture voltage during the switching process, we overcome the issue of excessive displacement currents at the detector during polarity switching, which usually lead to overdriving the output signal of the high-gain transimpedance amplifier. Furthermore, mechanical aperture grid oscillations caused by polarity switching were also reduced through the ramped aperture voltage. This enables a polarity switching time of only 7 ms at a drift voltage of 8 kV and a drift length of 103 mm, leading to a high resolving power of RP= 117. Requiring 50 ms to acquire a pair of positive and negative spectrum, the IMS achieves an acquisition rate of 20 Hz. It reaches limits of detection of 20 pptvfor dimethyl methylphosphonate and 40 pptvfor methyl salicylate. For demonstration, different hop varieties were investigated and could be clearly differentiated by considering both, the positive and negative spectra.

• Flash-annealing of Cu 47.5 Zr 47.5 Al 5 and Cu 46.5 Zr 48 Al 4 Nb 1.5 metallic-glass ribbons. • Cu 10 Zr 7 precipitates enhance mechanical performance of obtained composites materials. • Nanocrystalline materials have good corrosion resistance in NaCL and H 2 SO 4 solutions. Metallic-glass–crystal composites of Cu 47.5 Zr 47.5 Al 5 and Cu 10 Zr 7 -reinforced Cu 46.5 Zr 48 Al 4 Nb 1.5 nanocrystalline materials are obtained by flash-annealing of metallic-glass ribbons. In situ high-energy X-ray diffraction reveals the deformation mechanism of the alloys upon tensile loading. For the composites and nanocrystalline materials, a small remaining amount of the metallic glass and/or the presence of the Cu 10 Zr 7 phase significantly increase the value of yield stress while maintaining good tensile ductility. In general, the obtained materials exhibit a reversible martensitic transformation (MT) between the B2 CuZr and B19′/B33 phases during tensile loading and unloading. However, the reversibility of MT depends on the alloy composition, crystalline phases, and the number of (un)loading cycles. Serrated-like fluctuations on tensile stress-strain curves and a sign of twinning in the Cu 10 Zr 7 crystals are found after yielding in the Cu 10 Zr 7 -reinforced Cu 46.5 Zr 48 Al 4 Nb 1.5 nanocrystalline materials. Electrochemical measurements show that Cu 46.5 Zr 48 Al 4 Nb 1.5 nanocrystalline material has good corrosion resistance in NaCl and H 2 SO 4 solutions, even better than the parent metallic glasses in some aspects. [Display omitted] [ABSTRACT FROM AUTHOR]

Early Barrett cancer can be curatively treated by endoscopic resection. The choice of the resection technique, however—endoscopic mucosal resection (EMR) or submucosal dissection (ESD)—largely depends on the assumed infiltration depth as judged by the endoscopist. However, the accuracy of endoscopic diagnosis of the degree of cancer infiltration is not known. Three to four high‐quality images (both in overview and close‐up) from 202 of early Barrett esophagus cancer cases (82% men, mean age 66.9 years) were selected from our endoscopy database (73.3% stage T1a and 26.7% in stage T1b). Images were shown to 9 Barrett esophagus experts, with patients' clinical data (age, sex, Barrett esophagus length) and biopsy results. The experts were asked to predict infiltration depth (T1b vs. T1a), and to suggest the appropriate endoscopic resection technique (EMR or ESD, or surgery). Interobserver variability (kappa values) was also determined for these parameters. Overall positive (PPV) and negative predictive values (NPV) to diagnose T1b versus T1a infiltration were 40.7% (95% CI: 36.7, 44.8) and 79.8% (95% CI: 77.5, 81.9), respectively; kappa value was 0.41. Paris classification (kappa 0.51) and suggested treatment also varied between experts. In a post hoc analysis, only the correlation between lesions classified as invisible or flat according to the Paris classification (IIB; 25% of all cases) and the suggested resection technique was better: In this subgroup, EMR was recommended in >80% of cases, with a high complete (basal R0) resection rate (mean of 88.1%). Precise endoscopic distinction between mucosal and submucosal involvement of Barrett esophagus cancer by experts as a basis for choosing the resection technique has limited predictive values and high interobserver variability. It seems that mainly invisible/flat lesions may result in good resection outcomes when treated by EMR, but this stratification strategy has to be assessed in further studies.

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine–hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

Dieser Beitrag in der Zeitschrift „Gruppe. Interaktion. Organisation. (GIO)“ führt in das Konzept der Ambiguitätstoleranz ein und verdeutlicht seine Relevanz im gegenwärtigen Zeitgeschehen. Ambiguitätstoleranz wird gemeinhin als wichtige Kompetenz auch im organisationalen Kontext gesehen, um Mehrdeutigkeiten und Unsicherheiten auszuhalten und in krisenhaften Zeiten handlungsfähig zu bleiben. Nachdem die Autor:innen des Beitrags detaillierter auf die Entstehung des aus den 1940ern stammenden Konzeptes eingegangen sind, verdeutlichen sie seine hohe gesellschaftspolitische Relevanz anhand des Diskurses um die documenta 15, des Streites um den Konflikt in Nahost und der Reaktionen auf die Enthüllungen von Correctiv zur Neuen Rechten. Daran anknüpfend zeigen sie auf, was sich daraus für den Organisationskontext ableiten lässt. Abschließend widmet sich der Beitrag der Frage der Erlernbarkeit von Ambiguitätstoleranz und zeigt dessen Voraussetzungen auf.