Feasibility of implementation of the early tumor shrinkage as a potential predictive marker to daily clinical practice in patients with RAS wild type metastatic colorectal cancer, treated with cetuximab - a non-interventional observational study.

BACKGROUND: With the aim to show the feasibility of early tumor shrinkage (ETS) concept implementation into daily clinical practice in the Czech Republic, a non-interventional, multicentric, single arm, prospective study in real world set-up was performed. MATERIAL AND METHODS: The study objectives were to explore the time interval from the treatment starting date to the date of the first radiographic control (TFRC) and evaluate the proportion of patients who achieved ≥ 20% tumor regression within the first 8 weeks of first-line therapy, in the real-world settings. RESULTS: The medians of TFRC in all individual participating centers were > 12 weeks (range 14.0-36.4 weeks). TFRC ≤ 8 weeks was reported for only 3% of patients in the cohort with first-line therapy, and there were only 3 patients (1%) who achieved tumor regression of ≥ 20% by day 60 (8.6 weeks). CONCLUSION: These findings indicate that the basic time parameter of ETS could not realistically be employed in routine oncology care of patients with metastatic colorectal cancer (mCRC) in the Czech Republic, unless there would be a strict request to perform TRFC by week 8 since the initiation of the therapy. In addition, the frequency of objective tumor response to first-line therapy with cetuximab + chemotherapy was evaluated. Based on the relative regression in the sum of diameters of measurable metastatic lesions, unconfirmed partial responses were achieved in 42.4 % and unconfirmed complete response in 8.6% of patients, altogether corresponding to the overall response rate of 51% with first-line therapy. The frequency of responses was higher among patients with left than right sided primary tumors. It seems that the regimen of cetuximab/FOLFOX might be more active in frontline therapy of right sided RAS wild type mCRC than cetuximab/FOLFIRI.

[Health economic evaluation of rehabilitative short-term care : Analysis of the costs of geriatric patients with and without rehabilitative short-term care after inpatient hospital stay]. / Gesundheitsökonomische Evaluation einer rehabilitativen Kurzzeitpflege : Ermittlung der Kosten von geriatrischen Patienten mit und ohne rehabilitative Kurzzeitpflege nach stationärem Krankenhausaufenthalt.

BACKGROUND: Geriatric patients requiring rehabilitation and admitted to short-term care after an acute inpatient hospital stay seldom receive rehabilitative services later. Rehabilitative short-term care (REKUP) supplements short-term care with rehabilitative measures, aiming to prevent functional restrictions and long-term care. STUDY OBJECTIVE: To conduct a cost and cost-effectiveness analyses of REKUP and provide data for a nationwide rollout. MATERIAL AND METHODS: A non-randomized controlled prospective study was carried out. The intervention group (IG) was paired 1:2 with a control group (KG), resulting in the formation of three collectives with follow-up periods of either 30, 90 or 180 days (each with IG and KG). Using administrative claims data from the AOK Baden-Württemberg, the mean total costs from the perspective of the health insurance were calculated. A potential impact of the intervention on costs was analyzed using the difference in differences approach. RESULTS: The analysis comprised 129 patients (IG 43; KG 86). During the follow-up periods, the IG presented higher rates of rehabilitation and lower rates of long-term care and mortality. Regarding costs, no statistically significant differences were found between the IG and KG in any of the three collectives. For nursing care and medication costs, costs were significantly higher in the follow-up period for the KG, whereas costs for rehabilitation were significantly higher for the IG (p < 0.001). DISCUSSION: Patients receiving REKUP utilize rehabilitation services more often and have a lower likelihood of requiring nursing care or dying with no statistically significant differences in costs. There are potential advantages of REKUP in the target population, which warrant further investigation due to methodological limitations.

A facile strategy for tuning the density of surface-grafted biomolecules for melt extrusion-based additive manufacturing applications.

Melt extrusion-based additive manufacturing (ME-AM) is a promising technique to fabricate porous scaffolds for tissue engineering applications. However, most synthetic semicrystalline polymers do not possess the intrinsic biological activity required to control cell fate. Grafting of biomolecules on polymeric surfaces of AM scaffolds enhances the bioactivity of a construct; however, there are limited strategies available to control the surface density. Here, we report a strategy to tune the surface density of bioactive groups by blending a low molecular weight poly(ε-caprolactone)5k (PCL5k) containing orthogonally reactive azide groups with an unfunctionalized high molecular weight PCL75k at different ratios. Stable porous three-dimensional (3D) scaffolds were then fabricated using a high weight percentage (75 wt.%) of the low molecular weight PCL5k. As a proof-of-concept test, we prepared films of three different mass ratios of low and high molecular weight polymers with a thermopress and reacted with an alkynated fluorescent model compound on the surface, yielding a density of 201-561 pmol/cm2. Subsequently, a bone morphogenetic protein 2 (BMP-2)-derived peptide was grafted onto the films comprising different blend compositions, and the effect of peptide surface density on the osteogenic differentiation of human mesenchymal stromal cells (hMSCs) was assessed. After two weeks of culturing in a basic medium, cells expressed higher levels of BMP receptor II (BMPRII) on films with the conjugated peptide. In addition, we found that alkaline phosphatase activity was only significantly enhanced on films containing the highest peptide density (i.e., 561 pmol/cm2), indicating the importance of the surface density. Taken together, these results emphasize that the density of surface peptides on cell differentiation must be considered at the cell-material interface. Moreover, we have presented a viable strategy for ME-AM community that desires to tune the bulk and surface functionality via blending of (modified) polymers. Furthermore, the use of alkyne-azide "click" chemistry enables spatial control over bioconjugation of many tissue-specific moieties, making this approach a versatile strategy for tissue engineering applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s42242-024-00286-2.

Artificial Space Weathering to Mimic Solar Wind Enhances the Toxicity of Lunar Dust Simulants in Human Lung Cells.

During NASA's Apollo missions, inhalation of dust particles from lunar regolith was identified as a potential occupational hazard for astronauts. These fine particles adhered tightly to spacesuits and were unavoidably brought into the living areas of the spacecraft. Apollo astronauts reported that exposure to the dust caused intense respiratory and ocular irritation. This problem is a potential challenge for the Artemis Program, which aims to return humans to the Moon for extended stays in this decade. Since lunar dust is "weathered" by space radiation, solar wind, and the incessant bombardment of micrometeorites, we investigated whether treatment of lunar regolith simulants to mimic space weathering enhanced their toxicity. Two such simulants were employed in this research, Lunar Mare Simulant-1 (LMS-1), and Lunar Highlands Simulant-1 (LHS-1), which were added to cultures of human lung epithelial cells (A549) to simulate lung exposure to the dusts. In addition to pulverization, previously shown to increase dust toxicity sharply, the simulants were exposed to hydrogen gas at high temperature as a proxy for solar wind exposure. This treatment further increased the toxicity of both simulants, as measured by the disruption of mitochondrial function, and damage to DNA both in mitochondria and in the nucleus. By testing the effects of supplementing the cells with an antioxidant (N-acetylcysteine), we showed that a substantial component of this toxicity arises from free radicals. It remains to be determined to what extent the radicals arise from the dust itself, as opposed to their active generation by inflammatory processes in the treated cells.

Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

UN ETEROCLITO BABUINO: On Giordano Bruno's Candelaio and the Infinitization of the Sexes.

Giordano Bruno (Nola 1548 - Rome 1600) published in 1582 Candelaio, a comedy that anticipates the core arguments he developed in the six dialogs written in volgare during the philosopher's stay in England (1583-1585). In the comedy, the term candelaio (candlebearer) is deployed not only as a trope for light and illumination, but also as a slang designation for sodomite. Thus, sexual dissident Bonifacio, the tragicomic personage to which the title refers, brings to light the mostly unavowed or denigrated, albeit ineradicable complexities of every sexual individuality. In this framework, the personality, lifestyle, and views of disruptive Bonifacio/Candelaio serve as narrative support for a critical stance aiming at undoing the validity claims of the man/woman dichotomy. At the antipodes of the finitization of sexuality fostered by Christian creationism, Bruno's sexual approach is framed within a conception of "natura naturante," the all-pervasive, inexhaustible and animating power, which enables the emergence of utterly diversified beings throughout the infinitude of the existing worlds. Having dismantled the epistemic pretentions of sexual binarity and its possible closed supplementations, Bruno effectively frees Bonifacio's sexual heteroclisis from the stigma of unnaturalness. Notwithstanding the trailblazing traits of Bruno's sexual thought and its ontological framework, Brunian scholarship to the present has ignored that the philosopher from Nola posed the arguably most profound and consistent challenge to binary sexuality and its finite suppletions in pre-Darwinian Modernity. In view of the critiques of patriarchy and anti-feminism that began to develop at the turn to the twentieth century, it is striking that no systematic effort has been undertaken to relate Bruno's principled reversion of the form/matter hierarchy to his advocacy for the axiological restauration of femaleness in the masculinist-centered culture of the West. In accordance with Bruno's explicit design to "turn upside down the reversed world," his philosophy seeks to reveal the endless profusion of sexual forms not as creations of an omnipotent paternal figure, but as emergences from an inexhaustible source, which he signally terms "the maternal womb of Nature."

A sinterless, low-temperature route to 3D print nanoscale optical-grade glass.

Three-dimensional (3D) printing of silica glass is dominated by techniques that rely on traditional particle sintering. At the nanoscale, this limits their adoption within microsystem technology, which prevents technological breakthroughs. We introduce the sinterless, two-photon polymerization 3D printing of free-form fused silica nanostructures from a polyhedral oligomeric silsesquioxane (POSS) resin. Contrary to particle-loaded sacrificial binders, our POSS resin itself constitutes a continuous silicon-oxygen molecular network that forms transparent fused silica at only 650°C. This temperature is 500°C lower than the sintering temperatures for fusing discrete silica particles to a continuum, which brings silica 3D printing below the melting points of essential microsystem materials. Simultaneously, we achieve a fourfold resolution enhancement, which enables visible light nanophotonics. By demonstrating excellent optical quality, mechanical resilience, ease of processing, and coverable size scale, our material sets a benchmark for micro- and nano-3D printing of inorganic solids.

TIMP-1 as a biomarker in obstructive sleep apnea: screening, monitoring, risk stratification, and a step towards precision medicine.

OBJECTIVE: The diagnosis of obstructive sleep apnea (OSA) is a complex time- and resource-intensive diagnostic procedure. Since tissue inhibitors of matrix metalloproteinases (TIMP's) are involved in various pathophysiological processes and are correlated with a high cardiovascular risk, TIMP's appear to be a suitable candidate for an OSA-biomarker. PATIENTS AND METHODS: In a prospective controlled diagnostic study, TIMP-1 serum levels of 273 OSA-patients and controls were analyzed for correlation with OSA severity, BMI, age, sex, cardio-/ cerebrovascular comorbidities. Furthermore, longitudinal medium- and long-term effects of CPAP-treatment (n=15) on TIMP-1-levels were investigated. RESULTS: TIMP-1 was clearly linked to OSA as well as to disease severity (mild, moderate, severe; each p<0.001) and was not influenced by age, gender, BMI, or cardio-/cerebrovascular comorbidities. ROC curve analysis revealed an AUC of 0.91 ± 0.017 SE (p<0.001), suggesting a TIMP-1 cut-off value of 75 ng/ml (sensitivity 0.78; specificity 0.91) being especially sensitive for patients with severe OSA (sensitivity 0.89; specificity 0.91). The likelihood ratio was 8.88, while the diagnostic odds ratio was 37.14. CPAP-treatment led to a significant decrease of TIMP-1 after 6-8 months (p=0.008). CONCLUSIONS: TIMP-1 seems to fulfill the preconditions for a circulating OSA-biomarker: disease-specific with a mandatory presence in affected patients, reversible on treatment, reflects disease severity and provides a cutoff value between the healthy state and disease. In the clinical routine, TIMP 1 may help to stratify the individual OSA-associated cardiovascular risk and to monitor the treatment response to CPAP-therapy as a further step towards providing a personalized therapy.

Post-acute COVID-19 geriatric rehabilitation : A European perspective.

Coronavirus disease 2019 (COVID-19) poses a threat to the health and independence of older people in particular. In this article we elaborate on the content and importance of post-acute COVID-19 geriatric rehabilitation from a European perspective. We explain the geriatric rehabilitation paradox and how this can and should be solved. We also present what post-acute COVID-19 geriatric rehabilitation should entail. This might not only help us to develop better geriatric rehabilitation services, but it should also inform pandemic preparedness in the future.

What progress has been made in treatment of immunocompromised COVID-19 patients?

While immunocompromised patients are at very high risk of developing severe COVID 19, few of them have been enrolled in studies aimed at evaluating treatments. In the early stages of research on this disease, glucocorticoid therapy became the standard of care for patients requiring oxygen supplementation. It has been demonstrated that the neutralizing monoclonal antibody combination of Casirivimab and Imdevimab reduced (by 28 days) mortality in COVID-19 patients admitted to hospital who were seronegative at baseline, but not in those who were seropositive. There is still a need to determine the place of available various antivirals (Molnupiravir or Nirmatrelvir plus Ritonavir) and passive immunotherapies (Sotrovimab…) as well as convalescent plasma therapy in immunocompromised settings.

SARS-CoV-2 genetic diversity: Its impact on vaccine efficacy.

SARS CoV 2 S-glycoproteins play a crucial role in the entry steps of viral particles. Due to their surface location, they are the main target for host immune responses and the focus of most vaccine strategies. The D614G mutation identified in late January became dominant during March 2020, rendering SARS-CoV-2 more infectious. In April 2020, the Alpha, Beta and Gamma variants emerged simultaneously in Asia, South Africa, and South America, respectively. They were 1.6 to 2 times more transmissible than the ancestral strain. The currently dominant Omicron variant (BA.2) is not a direct descendant from the D614G lineage, but rather emerged from the BA.1 variant (as did BA.4 and BA.5). It is substantially different from all the other variants. It presents significantly reduced susceptibility to antibody neutralization: after 2 doses of mRNA-vaccine, neutralizing titers to Omicron are 41 to 84 times lower than neutralization titers to D614G. That said, a booster dose of mRNA-vaccine increases Omicron neutralization titers and reduces the risk of severe infection.

Attitudes of French adults toward COVID-19 vaccination.

Reticence toward COVID-19 vaccination is more prevalent among women, people with low income, people who feel close to parties on the Far Right and Far Left and people who feel close to no party at all. It illustrates a mistrust of state institutions and policy-makers in general. The arguments in favor of Covid vaccine refusal are safety concern, and the contention that COVID is a mild disease. That said, vaccine hesitancy is vaccine-specific, with a major difference between Pfizer/Moderna and Oxford-AstraZeneca vaccines. Aside from vaccine hesitancy, vaccination intention rate has approached 80%.

What are the prospects for durable immune control?

During the SARS CoV-2 primary infection, the neutralizing antibodies focused against the spike (S) glycoproteins are responsible for blockage of virus-host cell interaction. The cellular response mediated by CD4+ and CD8+ T-cells is responsible for control of viremia. Immune memory against SARS-CoV-2 depends on virus type, replication kinetics and route of penetration. The formation and persistence of germinal centers are critical for the generation of affinity-matured plasma cells and memory B cells capable of mediating durable immunity. They can persist up to 30 weeks after vaccination and several months after infection. Heterogeneity in the longevity of the vaccination-induced GC response is significant.

[Integrated care concepts and multidisciplinary process chains in a radiological context]. / Integrierte Behandlungskonzepte und multidisziplinär organisierte Prozessketten im radiologischen Kontext.

Modern patient-centered and cost-efficient care concepts in hospitals require the mapping of multidisciplinary process chains into clinical pathways. Clinical decision support systems and operations research methods use algorithms to classify patients into homogeneous groups and to model a complete clinical pathway for scheduling individual procedures. An improvement of the economic situation of the care facility can be achieved through improved resource utilization, reduced patient waiting times and a shortening of the length of stay. The interdisciplinary use of centrally stored interoperable information and comprehensive care management via information technology (IT) services lay the foundation for the dissolution of traditional IT system architectures in medicine and the development of flexibly integrable modern system platforms. New IT approaches such as the semantically standardized definition of procedures and resource properties, the use of clinical decision support systems and the use of service-oriented system architectures form the basis for the deep integration of radiology services into comprehensive interdisciplinary care concepts.