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Background & aims: The CFTR-modulating therapy Elexaftor – Tezacaftor - Ivacaftor (ETI) has been widely prescribed since its approval in 2020 in the European Union. The aim of this study was to methodically evaluate the effects of an ETI treatment on clinical, biochemical data and Pseudomonas colonization in order to demonstrate its efficacy. Methods: This prospective monocentric study comprised 69 patients diagnosed with cystic fibrosis aged at least 12 years and treated with ETI between September 2020 and November 2021. Clinical and laboratory data of each patient and study visit were collected before and after 24 weeks of ETI treatment. Follow-up status of Pseudomonas aeruginosa (PsA) colonization was assessed after one year of therapy by regularly determined sputum or throat swab samples. Results: Marked improvements biochemical markers of systemic inflammation as white blood cell count, levels of immunoglobulins A, G and M and albumin within 24 weeks of therapy were observed. ETI treatment proved to be effective as seen by amelioration of lung function and sweat chloride concentration. Assessment of PsA colonization status revealed a conversion from a positive to negative detection in 36% of the cases after one year of therapy. Conclusions: ETI treatment effectively improves systemic inflammation parameters and shows promising results in PsA status conversion.

Abstract Background Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. Case presentation We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. Conclusions The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.

Materialist theories of disability link disability and labor, hypothesizing that under neoliberalism, disability stigma contributes to labor market precarity. These claims have not been evaluated empirically and the mediating role of the state remains underspecified. Ethnographic fieldwork in a job training program for people with psychiatric disabilities reveals two contradictions in the welfare state treatment of disability. First, disability benefits are set at low levels, yet means-testing limits earnings, channeling people with disabilities into low-wage jobs. Second, contradictory imperatives attached to state funding incentivize placement in temporary jobs. These welfare state contradictions produce disabled workers as a precarious labor force. [ABSTRACT FROM AUTHOR]

The article in the journal "Frontiers in Earth Science" explores contemporary studies on cold seeps, hydrothermal vents, mud volcanoes, and related seafloor features. These features provide insights into deep processes that are typically inaccessible to scientists. The research emphasizes multidisciplinary approaches to studying seafloor fluid emissions, highlighting the importance of geologic, physical, chemical, and biological processes in these environments. The studies cover a wide range of topics, including microbial processes, fluid dynamics, mineralization, and the role of seafloor emissions in global biogeochemical cycles. [Extracted from the article]

How does work come to be constructed as a service to the worker? In the United States, the payment of subminimum wages to disabled workers has been legal since 1938 and was entrenched by 1986 legislation eliminating the previously mandated floor of 50 percent of the minimum wage. This article draws on primary historical materials to explain the passage of these amendments, which I analyze as a case of delaborization, a process through which work is mystified as such and reclassified as something else (e.g., service). I find that the managers of segregated workshops for disabled manual laborers rose to control disability employment policy in the aftermath of deinstitutionalization. Professionals mobilized disability stigma to frame the subminimum wage as a social welfare issue subject to their expertise and to lobby successfully for its entrenchment. Weaknesses in the disability–labor coalition enabled this seizure of jurisdiction. This research illuminates professional expertise, the withdrawal of labor unions, and identity-based stigma as major mechanisms driving delaborization, an important contemporary influence on the organization of work. The case of the subminimum wage thus develops sociological literatures on labor, disability, and politics. [ABSTRACT FROM AUTHOR]

Bedrock geology from Antarctica remains largely unknown since it is hidden beneath thick ice sheets. Geophysical methods such as gravity and magnetic inverse modelling provide a framework to infer crustal rock properties indirectly in Antarctica. However, due to limited availability of rock samples, validation against direct geological information is challenging. We present a new rock property catalogue containing density and susceptibility measurements on 320 rock samples from northern Victoria Land. This catalogue is used to assess the reliability of local and regional scale inverse results, including a new local high resolution magnetic inversion in the Mesa Range region and a previously published regional scale joint inversion of gravity and magnetic data in northern Victoria Land and the Wilkes Subglacial Basin. We compare our density and susceptibility measurements to global and local measurements from the literature to access the correlation to rock types and geological units. Furthermore, the measured values are compared against inverted values. The close correspondence between inverted and measured rock properties allows us to predict locations of rock types where currently such information is missing. The utility of measured susceptibility and density relationships for interpreting inversion output provides a strong incentive to incorporate local rock samples into geophysical studies of subglacial geology across Antarctica. [ABSTRACT FROM AUTHOR]

Cell‐penetrating peptides (CPPs) have been explored as versatile tools to transport various molecules into cells. The uptake mechanism of CPPs is still not clearly understood and most probably depends on several factors like the nature of the CPP itself, the attached cargo, the investigated cell system, and other experimental conditions, such as temperature and concentration. One of the first steps of internalization involves the interaction of CPPs with negatively charged molecules present at the outer layer of the cell membrane. Recently, thiol‐mediated uptake has been found to support the effective translocation of sulfhydryl‐bearing substances that would actually not be cell‐permeable. Within this work, we aimed to understand the relevance of thiol reactivity for the uptake mechanism of cysteine‐containing CPPs that we have developed previously in our group. Therefore, we compared the two peptides, sC18‐Cys and CaaX‐1, in their single reduced and dimeric disulfide versions. Cytotoxicity, intracellular accumulation, and impact on the internalization process of the disulfides were investigated in HeLa cells. Both disulfide CPPs demonstrated significantly stronger cytotoxic effects and membrane activity compared with their reduced counterparts. Notably, thiol‐mediated uptake could be excluded as a main driver for translocation, showing that peptides like CaaX‐1 are most likely taken up by other mechanisms. [ABSTRACT FROM AUTHOR]

Provides society information that may include news, reviews or technical notes that should be of interest to practitioners and researchers. [ABSTRACT FROM AUTHOR]

Depression affects several aspects of life, including socioeconomic status, relationships, behavior, emotions, and overall health. The etiology of depression is complex and influenced by various factors, with obesity emerging as a significant contributor. This narrative review aims to investigate the factors associated with the development of depression, with a particular focus on the role of obesity. The literature search was conducted on PubMed, Embase, and PsycINFO from May to July 2024. The review highlights the impact of environmental and socioeconomic conditions; lifestyle choices, including physical activity and dietary habits; stress; traumatic experiences; neurotransmitter imbalances; medical and psychological conditions; hormone fluctuations; and epigenetic factors on depression. A key emphasis is placed on the inflammatory processes linked to obesity, which may drive the bidirectional relationship between obesity and depression. The findings suggest that obesity is associated with an increased risk of depression, potentially due to chronic inflammation, neurochemical dysregulation, and the emotional and social challenges related to weight stigma and obesity management. Understanding these interconnected factors is important for developing targeted interventions to address both obesity and depression, leading to improved quality of life for those affected. [ABSTRACT FROM AUTHOR]

Abstract Antibody therapeutics can be associated with unwanted immune responses resulting in the development of anti‐drug antibodies (ADA). Optimal methods to evaluate the potential effects of ADA on clinical outcomes in oncology are not well established. In this study, we assessed efficacy and safety, based on ADA status, in patients from over 10 clinical trials that evaluated the immune checkpoint inhibitor atezolizumab as a single agent or as combination therapy for several types of advanced cancers. ADA can only be observed post randomization, and imbalances in baseline prognostic factors can confound the interpretation of ADA impact. We applied methodology to account for the confounding effects of baseline clinical characteristics and survivorship bias on efficacy. Adjusted meta‐analyses revealed that despite numerical differences in overall survival and progression‐free survival between ADA‐positive and ADA‐negative patients from some studies, ADA‐positive patients from studies with an overall treatment effect derived benefit from atezolizumab, compared with their adjusted controls. Based on large, pooled populations from atezolizumab monotherapy or combination studies, unadjusted descriptive analyses did not identify a clear relationship between ADA status and frequency or severity of adverse events. Data also suggested that any ADA impact is not driven by neutralizing activity. Collectively, this exploratory analysis suggests that the potential for ADA development should not impact treatment decisions with atezolizumab.

Abstract Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti‐drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti–PD‐L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13–54%) developed treatment‐emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA‐positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure‐response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.

Die weltweite Einführung strenger Vorschriften zur Eindämmung der Pandemie der Coronavirus-Erkrankung (SARS-CoV-2, Covid-19) hatte spürbare Folgen für das soziale Leben. Maßnahmen wie die Verringerung von Sitzplätzen in Innenräumen, soziale Distanz, die obligatorische Verwendung von Masken und „Bleib zu Hause“-Kampagnen haben die Interaktionen zwischen Menschen drastisch reduziert. Diese Maßnahmen erwiesen sich als wirksam, um die Covid-19-Infektionsraten zu senken und damit die Ausbreitung des Virus zu verhindern (1,2). Verschiedene andere Krankheitserreger, Viren und Bakterien, werden jedoch auf ähnliche Weise von Mensch zu Mensch übertragen (3,4). Dies gilt beispielsweise für viele Erreger, die Infektionen der Atemwege und des Darms verursachen (5). Während der Covid-19-Pandemie wurden einige nicht ansteckende akute Erkrankungen wie Schlaganfall und Myokardinfarkt seltener dokumentiert. Die Verhaltensänderung, die sich aus der Umsetzung strenger Hygieneregeln ergab, könnte auch zu einem „echten“ Rückgang der Raten von Nicht-Covid-19-Infektionskrankheiten geführt haben (5,6). Mit anderen Worten: Die Maßnahmen zur Bekämpfung der Covid-19-Pandemie könnten auch die Ausbreitung anderer Keime beeinflusst haben, die Atemwegsinfektionen (AI) und gastrointestinale Infektionen (GI) verursachen. Aus diesem Grund wollten die Autoren in der vorliegenden Studie die Häufigkeit dieser AI und GI während der Covid-19-Pandemie anhand von Daten aus einer großen Datenbank untersuchen, in die anonymisierte Behandlungsinformationen von Haus- sowie von Kinder- und Jugendärzten in Deutschland einfließen.

Tactile perception is an important modality for dexterous manipulation, but faces unique challenges in that the sensor has to wrap around the system. Biological skin solves these problems extremely well. Not only can it detect contacts, but it also grows on complex three-dimensional shapes, stretches with underlying soft tissue and around joints, and leaves enough space inside for other organs. Previous artificial sensors could only achieve different subsets of these features. We present a novel tactile sensor skin which is completely made from elastic silicone rubber and can stretch to multiple times its original length without damage. It can be produced in three-dimensional double-curved shapes, is thin enough to accommodate other robot components or human body parts, and it can measure forces and locations of multiple simultaneous contacts. We develop production methods and material formulations, algorithms for computer-aided design, compact readout electronics using small, low-power FPGAs, firmware, and software.

Na estratigrafia do Rio Grande do Sul as formações Santa Tecla e Tupanciretã foram consideradas preliminarmente pós Gondwânicas a partir de datações relativas. São interpretações originadas a partir de um limitado conjunto de dados, de caráter preliminar ou especulativo. Este estudo tem o objetivo de revisar e analisar estes trabalhos dispersos e através de novas observações envolvendo elementos morfotectônicos como a análise das drenagens, condicionantes geotectônicos e paleoclimáticos posicionar estas unidades no panorama geológico do sul do Brasil. Como delimitadores da proveniência e do posicionamento paleogeográfico das formações Santa Tecla e Tupanciretã destaca-se o Arco de Rio Grande e o soerguimento em domo do Escudo Sul-Riograndense. A associação de ambas as formações com as Superfícies Cimeiras de Caçapava e de Vacaria em conjunto com um histórico de inversão do relevo, assegura-lhes uma idade relativa no topo do Cretáceo Inferior a Superior. As caraterísticas litológicas e deposicionais possibilitam a inferência de deposição em ambiente semiárido, com transporte subaquoso e contribuição eólica, típicos de ambientes fluviais efêmeros intracratônicos. Com o conjunto de informações é possível traçar um paralelo com os grupos Bauru (Brasil) e Paisandú (Uruguai), que integram a Supersequência Bauru da Bacia do Paraná. As evidências indicam que as formações Santa Tecla e Tupanciretã pertencem a este contexto.

In response to warming climate, methane can be released to Arctic Ocean sediment and waters from thawing subsea permafrost and decomposing methane hydrates. However, it is unknown whether methane derived from this sediment storehouse of frozen ancient carbon reaches the atmosphere. We quantified the fraction of methane derived from ancient sources in shelf waters of the U.S. Beaufort Sea, a region that has both permafrost and methane hydrates and is experiencing significant warming. Although the radiocarbon-methane analyses indicate that ancient carbon is being mobilized and emitted as methane into shelf bottom waters, surprisingly, we find that methane in surface waters is principally derived from modern-aged carbon. We report that at and beyond approximately the 30-m isobath, ancient sources that dominate in deep waters contribute, at most, 10 ± 3% of the surface water methane. These results suggest that even if there is a heightened liberation of ancient carbon-sourced methane as climate change proceeds, oceanic oxidation and dispersion processes can strongly limit its emission to the atmosphere.

In human-robot collaboration scenarios with shared workspaces, a highly desired performance boost is offset by high requirements for human safety, limiting speed and torque of the robot drives to levels which cannot harm the human body. Especially for complex tasks with flexible human behavior, it becomes vital to maintain safe working distances and coordinate tasks efficiently. An established approach in this regard is reactive servo in response to the current human pose. However, such an approach does not exploit expectations of the human's behavior and can therefore fail to react to fast human motions in time. To adapt the robot's behavior as soon as possible, predicting human intention early becomes a factor which is vital but hard to achieve. Here, we employ a recently developed type of brain-computer interface (BCI) which can detect the focus of the human's overt attention as a predictor for impending action. In contrast to other types of BCI, direct projection of stimuli onto the workspace facilitates a seamless integration in workflows. Moreover, we demonstrate how the signal-to-noise ratio of the brain response can be used to adjust the velocity of the robot movements to the vigilance or alertness level of the human. Analyzing this adaptive system with respect to performance and safety margins in a physical robot experiment, we found the proposed method could improve both collaboration efficiency and safety distance.