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INTRODUCTION: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. MATERIALS AND METHODS: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). RESULTS: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DISCUSSION: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy. CLINICALTRIALS: gov: NCT03416244.
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Lions and their prey are threatened across most of their range and especially in West and Central Africa. Prey availability influences carnivore densities, social structure, prey preference and home ranges, and changes in prey are important for carnivore management. Scarcity of large prey in many West and Central African ecosystems has been described as leading to a preference for hunting smaller prey in smaller groups. Here we investigated the changes in prey selection of lions in Zakouma National Park (Chad), a protected area in Central Africa that showed significant recovery in wildlife numbers, by collecting feeding data through observations of lions on kills during monitoring drives and GPS cluster points of lion collars. Compared to similar data collected prior to this significant recovery, lions preferred larger prey and fed in larger groups. Our results show that diet shifts due to prey losses can be reversed with restoration of prey populations thanks to improved management, and we speculate that this may be true across large carnivores and across regions.
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Predictive maintenance is considered a proactive approach that capitalizes on advanced sensing technologies and data analytics to anticipate potential equipment malfunctions, enabling cost savings and improved operational efficiency. For journal bearings, predictive maintenance assumes critical significance due to the inherent complexity and vital role of these components in mechanical systems. The primary objective of this study is to develop a data-driven methodology for indirectly determining the wear condition by leveraging experimentally collected vibration data. To accomplish this goal, a novel experimental procedure was devised to expedite wear formation on journal bearings. Seventeen bearings were tested and the collected sensor data were employed to evaluate the predictive capabilities of various sensors and mounting configurations. The effects of different downsampling methods and sampling rates on the sensor data were also explored within the framework of feature engineering. The downsampled sensor data were further processed using convolutional autoencoders (CAEs) to extract a latent state vector, which was found to exhibit a strong correlation with the wear state of the bearing. Remarkably, the CAE, trained on unlabeled measurements, demonstrated an impressive performance in wear estimation, achieving an average Pearson coefficient of 91% in four different experimental configurations. In essence, the proposed methodology facilitated an accurate estimation of the wear of the journal bearings, even when working with a limited amount of labeled data.
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Climate change has been associated with both latitudinal and elevational shifts in species' ranges. The extent, however, to which climate change has driven recent range shifts alongside other putative drivers remains uncertain. Here, we use the changing distributions of 378 European breeding bird species over 30 years to explore the putative drivers of recent range dynamics, considering the effects of climate, land cover, other environmental variables, and species' traits on the probability of local colonisation and extinction. On average, species shifted their ranges by 2.4 km/year. These shifts, however, were significantly different from expectations due to changing climate and land cover. We found that local colonisation and extinction events were influenced primarily by initial climate conditions and by species' range traits. By contrast, changes in climate suitability over the period were less important. This highlights the limitations of using only climate and land cover when projecting future changes in species' ranges and emphasises the need for integrative, multi-predictor approaches for more robust forecasting.
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Aves , Cambio Climático , Animales , EcosistemaRESUMEN
BACKGROUND: Lipedema, diagnosed most often in women, is a progressive disease characterized by the disproportionate and symmetrical distribution of adipose tissue, primarily in the extremities. Although numerous results from in vitro and in vivo studies have been published, many questions regarding the pathology and genetic background of lipedema remain unanswered. METHODS: In this study, adipose tissue-derived stromal/stem cells were isolated from lipoaspirates derived from nonobese and obese donors with or without lipedema. Growth and morphology, metabolic activity, differentiation potential, and gene expression were evaluated using quantification of lipid accumulation, metabolic activity assay, live-cell imaging, reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, and immunocytochemical staining. RESULTS: The adipogenic potential of lipedema and nonlipedema adipose tissue-derived stromal/stem cells did not rise in parallel with the donors' body mass index and did not differ significantly between groups. However, in vitro differentiated adipocytes from nonobese lipedema donors showed significant upregulation of adipogenic gene expression compared with nonobese controls. All other genes tested were expressed equally in lipedema and nonlipedema adipocytes. The adiponectin/leptin ratio was significantly reduced in adipocytes from obese lipedema donors compared with their nonobese lipedema counterparts. Increased stress fiber-integrated smooth muscle actin was visible in lipedema adipocytes compared with nonlipedema controls and appeared enhanced in adipocytes from obese lipedema donors. CONCLUSIONS: Not only lipedema per se but also body mass index of donors affect adipogenic gene expression substantially in vitro. The significantly reduced adiponectin/leptin ratio and the increased occurrence of myofibroblast-like cells in obese lipedema adipocyte cultures underscores the importance of attention to the co-occurrence of lipedema and obesity. These are important findings toward accurate diagnosis of lipedema. CLINICAL RELEVANCE STATEMENT: Our study highlights not only the difficulty in lipedema diagnostics but also the tremendous need for further studies on lipedema tissue. Although lipedema might seem to be an underestimated field in plastic and reconstructive surgery, the power it holds to provide better treatment to future patients can not be promoted enough.
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Leptina , Lipedema , Humanos , Femenino , Leptina/metabolismo , Lipedema/diagnóstico , Lipedema/patología , Adiponectina/metabolismo , Adipocitos/fisiología , Obesidad/complicaciones , Células CultivadasRESUMEN
Interpretation of whole-genome sequencing (WGS) data for foodborne outbreak investigations is complex, as the genetic diversity within processing plants and transmission events need to be considered. In this study, we analyzed 92 food-associated Listeria monocytogenes isolates by WGS-based methods. We aimed to examine the genetic diversity within meat and fish production chains and to assess the applicability of suggested thresholds for clustering of potentially related isolates. Therefore, meat-associated isolates originating from the same samples or processing plants as well as fish-associated isolates were analyzed as distinct sets. In silico serogrouping, multilocus sequence typing (MLST), core genome MLST (cgMLST), and pangenome analysis were combined with screenings for prophages and genetic traits. Isolates of the same subtypes (cgMLST types (CTs) or MLST sequence types (STs)) were additionally compared by SNP calling. This revealed the occurrence of more than one CT within all three investigated plants and within two samples. Analysis of the fish set resulted in predominant assignment of isolates from pangasius catfish and salmon to ST2 and ST121, respectively, potentially indicating persistence within the respective production chains. The approach not only allowed the detection of distinct subtypes but also the determination of differences between closely related isolates, which need to be considered when interpreting WGS data for surveillance.
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Bird migrations are impressive behavioral phenomena, representing complex spatiotemporal strategies to balance costs of living while maximizing fitness. The field of bird migration research has made great strides over the past decades, yet fundamental gaps remain. Technologies have sparked a transformation in the study of bird migration research by revealing remarkable insights into the underlying behavioral, cognitive, physiological and evolutionary mechanisms of these diverse journeys. Here, we aim to encourage broad discussions and promote future studies by highlighting research fields that are characterized by major knowledge gaps or conflicting evidence, namely the fields of navigation, social learning, individual development, energetics and conservation. We approach each topic by summarizing the current state of knowledge and provide a future outlook of ideas and state-of-the-art methods to further advance the field. Integrating knowledge across these disciplines will allow us to understand the adaptive abilities of different species and to develop effective conservation strategies in a rapidly changing world.
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Evolución Biológica , Aves , Animales , Aves/fisiología , Migración Animal/fisiologíaRESUMEN
Non-linear processes are a key feature in the emerging field of spin-wave based information processing and allow to convert uniform spin-wave excitations into propagating modes at different frequencies. Recently, the existence of non-linear magnons at half-integer multiples of the driving frequency has been predicted for Ni80Fe20 at low bias fields. However, it is an open question under which conditions such non-linear spin waves emerge coherently and how they may be used in device structures. Usually non-linear processes are explored in the small modulation regime and result in the well known three and four magnon scattering processes. Here we demonstrate and image a class of spin waves oscillating at half-integer harmonics that have only recently been proposed for the strong modulation regime. The direct imaging of these parametrically generated magnons in Ni80Fe20 elements allows to visualize their wave vectors. In addition, we demonstrate the presence of two degenerate phase states that may be selected by external phase-locking. These results open new possibilities for applications such as spin-wave sources, amplifiers and phase-encoded information processing with magnons.
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Frequency multiplication is a process in modern electronics in which harmonics of the input frequency are generated in nonlinear electronic circuits. Devices based on the propagation and interaction of spin waves are a promising alternative to conventional electronics. The characteristic frequency of these excitations is in the gigahertz (GHz) range and devices are not readily interfaced with conventional electronics. Here, we locally probe the magnetic excitations in a soft magnetic material by optical methods and show that megahertz-range excitation frequencies cause switching effects on the micrometer scale, leading to phase-locked spin-wave emission in the GHz range. Indeed, the frequency multiplication process inside the magnetic medium covers six octaves and opens exciting perspectives for spintronic applications, such as all-magnetic mixers or on-chip GHz sources.
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When studying the current literature, one might get the impression that lipedema is a "modern" disease, with increasing incidence and augmenting prevalence throughout Western countries during the last decade. However, a quick look into older textbooks shows that disproportionate accumulation of fat in female bodies has long been known without being recognized as an independent disease. Nevertheless, it was not until 1940 that Allen and Hines described a "syndrome characterized by fat legs and orthostatic edema" in a seminal publication. The mere awareness that people who have lipedema are not just overweight but suffer from a yet poorly defined pathological condition, may be considered a decisive leap forward in the understanding of lipedema. A number of comprehensive publications have since dealt with the clinical presentation of lipedema and have provided the first clues towards the potential pathological mechanisms underlying its initiation and progression. Nevertheless, despite all effort that has been undertaken to unravel lipedema pathology, many questions have remained unanswered. What can be deduced with certainty from all experimental and medical evidence available so far is that lipedema is neither a cosmetic problem nor is it a problem of lifestyle but should be accepted as a serious disease with yet undetermined genetic background, which makes women's lives unbearable from both a physical and psychological point of view. To date, results from clinical inspections have led to the categorization of various types and stages of lipedema, describing how the extremities are affected and evaluating its progression, as demonstrated by skin alterations, adipose tissue volume increase and physical and everyday-behavioral impediments. There is accumulating evidence showing that advanced stages of lipedema are usually accompanied by excessive weight or obesity. Thus, it is not unreasonable to assume that the progression of lipedema is largely driven by weight gain and the pathological alterations associated with it. Similarly, secondary lymphedema is frequently found in lipedema patients at advanced stages. Needless to say, both conditions considerably blur the clinical presentation of lipedema, making diagnosis difficult and scientific research challenging. The present literature review will focus on lipedema research, based on evidence fromex vivo and in vitro data, which has accumulated throughout the last few decades. We will also open the discussion as to whether the currently used categorization of lipedema stages is still sufficient and up-to-date for the accurate description of this enigmatic disease, whose name, strangely enough, does not match its pathologic correlate.
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White-eared Kob, Kobuskobleucotis, Lichtenstein & Peters, 1853, is known to occur in the Gambela-Boma landscape in western Ethiopia and South Sudan. They live in herds and are generally found near water, in such places as plains, woodlands, swamps, and flood plains. We deployed 36 camera traps in Omo National Park and one of them took two images of a White-eared Kob. This is the first documentation from Omo National Park and showing that its range extends further to Omo than previously known and, therefore, the entire area (Gambella to Omo) can be considered as a range extension.
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African lions (Panthera leo) and African savanna (Loxodonta africana) and forest (L. cyclotis) elephants pose threats to people, crops, and livestock, and are themselves threatened with extinction. Here, we map these human-wildlife conflicts across Africa. Eighty-two percent of sites containing lions and elephants are adjacent to areas with considerable human pressure. Areas at severe risk of conflict (defined as high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species' ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations. Although a variety of alternative conflict-mitigation strategies could be deployed, we focus on assessing the potential of high-quality mitigation fences. Our spatial and economic assessments suggest that investments in the construction and maintenance of strategically located mitigation fences would be a cost-effective strategy to support local communities, protect people from dangerous wildlife, and prevent further declines in lion and elephant populations.
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Conservación de los Recursos Naturales/métodos , Elefantes , Interacción Humano-Animal , Leones , África , Distribución Animal , Crianza de Animales Domésticos , Migración Animal , Animales , Bovinos , Productos Agrícolas , Bosques , Pradera , Humanos , Dinámica Poblacional , Análisis EspacialRESUMEN
Weakly compressible particle-based discretization methods, utilized for the solution of the subsonic Navier-Stokes equation, are gaining increasing popularity in the fluid dynamics community. One of the most popular among these methods is the weakly compressible smoothed particle hydrodynamics. Since the dynamics of a single numerical particle is determined by fluid dynamic transport equations, the particle per definition should represent a homogeneous fluid element. However, it can be easily argued that a single particle behaves only pseudo-Lagrangian as it is affected by volume partition errors and can hardly adapt its shape to the actual fluid flow. Therefore, we will assume that the kernel support provides a better representative of an actual fluid element. By means of nonequilibrium molecular dynamics (NEMD) analysis, we derive isothermal transport equations for a kernel-based fluid element. The main discovery of the NEMD analysis is a molecular stress tensor, which may serve to explain current problems encountered in applications of weakly compressible particle-based discretization methods.
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Understanding the transmission phenomena of SARS-CoV-2 by virus-laden droplets and aerosols is of paramount importance for controlling the current COVID-19 pandemic. Detailed information about the lifetime and kinematics of airborne droplets of different size is relevant in order to evaluate hygiene measures like wearing masks but also social distancing and ventilation concepts for indoor environments. However, the evaporation process of expiratory droplets and aerosols is not fully understood. Consequently, the main objective of this study is to present evaporation characteristics of saliva droplets. An acoustic levitator is utilized in conjunction with microscopic imaging for recording the temporal evolution of the evaporation of saliva droplets under well-defined ambient conditions. Following the evaporation of the water content, a saliva droplet reaches a final size, which remains stable in the timescale of hours. By investigating numerous droplets of different size, it was found that the final droplet diameter correlates well to 20 % of the initial diameter. This correlation is independent of the ambient conditions for a temperature range from 20 °C to 29 °C and a relative humidity from 6 % to up to 65 %. The experimentally obtained evaporation characteristics are implemented into a numerical model, which is based on one-dimensional droplet kinematics and a rapid mixing evaporation model. By taking into account the evaporation-falling curve as presented by Wells, the significance of the experimental results for predicting the lifetime of saliva droplets and aerosols is demonstrated. The numerical predictions may be used to determine the impact of the droplet size and the ambient conditions on the transmission risks of infectious diseases like COVID-19.
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The measurement of the hydrogen desorption properties of sodium alanate (NaAlH4) powder compacts presents a particular challenge due to various material changes. Therefore, a parallel measurement method for both spectral and gravimetrical data acquisition has been developed. The optical tracking of such chemical reactions with gaseous exhalation requires a special apparatus, since hydrogen absorption/desorption alters the granularity and volume of the sample. The technique combines a commercial Fourier transform infrared spectrometer with a self-developed heatable attenuated total reflection (ATR) cuvette that maintains the indispensable close contact between the ATR medium and sample. In particular, strongly absorbing or scattering samples can be characterized with respect to their transmission changes and their mass loss, due to the evanescent field's penetration depth of a few micrometers into the bulk of the sample. In this work, the first and second desorption step of 2 mol. % CeCl3- and TiCl3-doped NaAlH4 compacts has been investigated. It was shown that the technique is able to monitor the hydrogen content in an alanate compact by means of the purely optically measured signal. In addition, a detailed analysis of the individual phase transformations was carried out. While the first reaction from the tetragonal to the monoclinic phase (NaAlH4=>Na3AlH6) showed a conversion nearly linear in time, the following reaction from the monoclinic to the hydride phase (Na3AlH6=>NaH) showed a nonlinear desorption process. The phase changes were accompanied by discontinuous intensity changes of certain absorption bands, as well as by nonconstant changes over time. Therefore, the second-phase conversion could be divided into two regions with different desorption behaviors. The optical and gravimetric measurements were supported by x-ray diffraction measurements to verify the composition of the materials after hydrogen desorption. For the technical application of this method, e.g., for use as a level sensor, these special optical features are essential and must be taken into account.
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PURPOSE: Concurrent progressive physiological dysregulation in different organ systems may be a driver of phenotypical frailty and is associated with morbidity and performance declines. In aging societies, health and performance of older workers are given increased scrutiny. However, there are few studies researching the effect of age on physiological dysregulation specifically in the working population and none for high-risk occupations with close medical supervision. Here, we aim to investigate this association cross-sectionally and longitudinally in a healthy sample of European helicopter emergency medical services pilots. METHODS: Using a retrospective cohort design, we constructed indices of (a) physiological dysregulation state (N = 52 participants) and (b) pace of change (N = 41 participants, average follow-up 7.9 years) based on measurements of 18 health risk-associated biomarkers, as documented in the participating pilots' aeromedical examination records. The relationship of these two indices with average age (range 27.9-60.6 years) and average baseline age (29.3-57.2 years), respectively, was modeled by weighted least squares regression, adjusting for region of origin, smoking, and medication. RESULTS: Longitudinally, dysregulation significantly increased over the follow-up period, but the pace of change did not increase with baseline age. Cross-sectionally, we observed a significant negative quadratic effect of age on physiological dysregulation state, with maximum estimated physiological dysregulation at ages 45-50. CONCLUSIONS: As hypothesized, progression of dysregulation over approximately 8 years is observable in a healthy occupational sample but it does not accelerate (i.e., does not increase with baseline age). Increases in dysregulation are counteracted by what appears to be a strong healthy worker survivor effect. The study shows that the development of physiological dysregulation in high-risk occupations differs from that in the general population and that physiological dysregulation indices may be helpful in reconciling safety concerns and fair treatment of aging workers in safety-critical jobs.
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Envejecimiento/fisiología , Biomarcadores/sangre , Pilotos/estadística & datos numéricos , Adulto , Distribución por Edad , Ambulancias Aéreas , Aeronaves , Servicios Médicos de Urgencia , Europa (Continente) , Indicadores de Salud , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Salud Laboral , Estudios RetrospectivosRESUMEN
With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state of the microvasculature in the brain. When the microvasculature does not function properly, ischemia, hypoxia, oxidative stress and related pathologic processes ensue, further damaging vascular and neural function. One of the most important and specialized functions of the brain microvasculature is the blood-brain barrier (BBB), which controls the movement of molecules between blood circulation and the brain parenchyma. In this review, we are focusing on tight junctions (TJs), the multiprotein complexes that play an important role in establishing and maintaining barrier function. After a short introduction of the cell types that modulate barrier function via intercellular communication, we examine how age, age related pathologies and the aging of the immune system affects TJs. Then, we review how the TJs are affected in age associated neurodegenerative disorders: Alzheimer's disease and Parkinson's disease. Lastly, we summarize the TJ aspects of Huntington's disease and schizophrenia. Barrier dysfunction appears to be a common denominator in neurological disorders, warranting detailed research into the molecular mechanisms behind it. Learning the commonalities and differences in the pathomechanism of the BBB injury in different neurological disorders will predictably lead to development of new therapeutics that improve our life as we age.