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Abstract Background For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16–26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. Trial registration ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

BackgroundPathologic staging is crucial in colorectal cancer (CRC). Unlike the majority of solid tumors, the current staging model does not use tumor size as a criterion. We evaluated the predictive and prognostic impact of primary tumor size on all stages of CRC.MethodsUsing the National Cancer Database (NCDB), we conducted an analysis of CRC patients diagnosed between 2010 and 2015 who underwent resection of their primary cancer. Univariate and multivariate analyses were used to identify predictive and prognostic factors, Kaplan-Meier analysis and Cox proportional hazards models for association between tumor size and survival.ResultsAbout 61,000 patients met the inclusion criteria. Median age was 63 years and majority of the tumors were colon primary (82.7%). AJCC stage distribution was: I - 20.1%; II - 32.1%; III - 34.7% and IV - 13.1%. The prognostic impact of tumor size was strongly associated with survival in stage III disease. Compared to patients with tumors 10cm (HR 1.95 (1.65-2.31; p

BackgroundHigh-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and 1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features.ConclusionHigh-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

Abstract Background Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. Methods We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. Results The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). Conclusions Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

BackgroundTumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied.MethodsThe National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan–Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received.ResultsA total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18–90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left vs right (5-year OS 76.2 vs 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in the left vs right (5-year OS 73.2 vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 vs 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) vs 48.4% (n = 6,905), and survival was better in the left vs right (5-year OS 67.0 vs 54.4%, p < 0.001).ConclusionSurvival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.

Background: Clinico-pathological high-risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is not established. The aim of this study is to determine the impact of high-risk features in clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA. Methods: Patients with pathological stage II AA between 2010 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor,

Background: Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. Methods: A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. Results: The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. Conclusions: A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

High drug costs due to supplier-induced demand (SID) obstruct healthcare accessibility in China. Drug prescriptions can generate markup-related profits, and the low prices of other medical services can lead to labor-force underestimations; therefore, physicians are keen to prescribe drugs rather than services. Thus, in China, a public hospital reform has been instituted to cancel markups and increase service prices.A retrospective pre/post-reform study was conducted in ZJ province to assess the impact of the reform on healthcare expenditures and utilization, ultimately to inform policy development and decision-making. The main indicators are healthcare expenditures and utilization.Post-reform, drug expenditures per visit decreased by 8.2% and 15.36% in outpatient and inpatient care, respectively; service expenditures per visit increased by 23.03% and 27.69% in outpatient and inpatient care, respectively. Drug utilization per visit increased by 5.58% in outpatient care and underwent no significant change in inpatient care. Both were lower than the theoretical drug-utilization level, which may move along the demand curve because of patient-initiated demand (PID); this indicates that SID-promoted drug utilization may decrease. Finally, service utilization per visit increased by 6% in outpatient care and by 13.10% in inpatient care; both were higher than the theoretical level moving along the demand curve, and this indicates that SID-promoted service utilization may increase.The reform reduces drug-prescription profits by eliminating drug markups; additionally, it compensates for service costs by increasing service prices. Post-reform, the SID of drug prescriptions decreased, which may reduce drug-resource waste. The SID of services increased, with potentially positive and negative effects: accessibility to services may be promoted when physicians provide more services, but the risk of resource waste may also increase. This warrants further research. It is recommended that comprehensive measures that control SID and promote physician enthusiasm be carried out concurrently.

Colorectal cancer is the third most common cancer in the Western population and has a 5-year overall survival of 5–10% when metastatic. Approximately 30% of the patients with metastatic colorectal cancer have limited disease apparently isolated to the liver and, if this can be resected, the 5-year overall survival is improved to 30–60%. Therefore, it is important to identify patients who have both resectable disease and those with initially unresectable tumors who can potentially be downsized with chemotherapy to allow resection. First-line doublet chemotherapy regimens lead to response rates of 50–60%, triplet chemotherapy regimens may result in a response rate of up to 70%, and biological agents may add to responses or induce morphologic changes that facilitate disease resection. Surgical advances in recent years have also increased resectability rates and have challenged prior rules of resectability. Local therapies including ablation and radiation, often performed in conjunction with resection, may further aid in control of disease. The aim of this article is to focus on the role of neoadjuvant therapy in the treatment of colorectal liver metastases.

Bone Morphogenetic Protein (BMP-4) was shown to down-regulate melanogenesis, in part, by decreasing the level of tyrosinase [Yaar et al. (2006) JBC:281]. Results presented here show that BMP-4 down-regulated the protein levels of TRP-1, PKC-β, and MCI-R. When paired cultures of human melanocytes were treated with vehicle or BMP-4 (25 ng/ml), MAPK/ERK were phosphorylated within one hour of BMP-4 treatment. Then the activated MAPK/ERK caused an acute phosphorylation of MITF, followed by proteosome-mediated degradation of MITF, the key transcription factor for melanogenic proteins [Wu et al. (2000) Gene & Development:14]. However, prolonged exposure of melanocytes to BMP-4 (up to 48 hours) caused a decrease in the level of MITF-M transcript. In addition, BMP-4 decreased the intracellular level of cAMP, the key regulator of MITF expression. These results demonstrate that BMP-4 activates MAPK/ERK signaling pathway to transiently activate MITF; however, chronic treatment of BMP-4 to melanocytes causes a down-regulation of the expression of MITF, possibly in a cAMP-dependent pathway.

Abstract Background Offshore wind energy (OWE) will play a significant role in achieving climate neutrality. For example, several scenarios for Germany (e.g., Kopernikus base, Kopernikus 1.5 degree, Prognos CN65, and CN60) depict substantial OWE annual installed capacity additions, especially after 2030. This tendency promotes OWE technology development as deployment expands, allowing manufacturers to gain expertise and optimize wind turbine construction. The global trend towards ever-larger components (e.g., hub height and rotor diameter) is critical to achieving higher-rated capacities. These aspects and others, such as wind quality, influence not only OWE annual electricity production but also its environmental performance. In addition, future supply chains might reduce their environmental impacts and enhance OWE climate change mitigation. In this paper, a prospective life cycle assessment (pLCA) is developed and applied exemplarily for a 9.5-MW offshore wind turbine (OWT) on the North Sea coast of Germany for the years 2030 and 2050. Considering that the current OWTs under construction in Europe have an average capacity of 10 MW, Germany plans to instal OWTs of 9.5-MW. This exemplary OWT describes the potential advances for offshore wind turbines in 2030 and 2050, considering component scale-up and learning effects. Yet, the methodology is adaptable to various installed capacities and regions. This approach allows us to analyse not only the potential future characteristics of wind turbines, but also future developments in OWE supply chains. Therefore, relevant parameters related to OWT construction and operation (e.g., rotor diameter, hub height, distance to the shore, lifetime, etc.) as well as prospective life cycle inventory data for background systems that reflect potential future developments in the broader economy are considered. In this way, scenarios (e.g., optimistic, moderate, and pessimistic) for OWE elucidate the expected environmental impacts, such as climate change, marine eutrophication, and abiotic depletion potential, in 2030 and 2050. Results The findings describe the variability of the environmental impacts of a 9.5-MW offshore wind turbine representing the technologies expected to be available in Germany in 2030 and 2050 and show that climate change impacts could vary between 7 and 18 g CO2-eq per kWh produced in 2030 and between 5 and 17 g CO2-eq per kWh in 2050. However, marine eutrophication could experience a significant increase (100% increase), depending on the consideration of hydrogen as a fuel in the electricity mix, as demonstrated in the climate-neutral scenarios adopted for Germany. Overall, construction efficiency improvements in 2050 might reduce the required materials, leading to a 6% decrease in abiotic depletion potential compared to 2030 values. Conclusions This paper highlights the need to consider temporal improvements in LCA studies, particularly when assessing the environmental impacts of offshore wind turbines. The complex nature and rapid growth of offshore wind technology require a comprehensive life cycle approach to deepen our understanding of its potential environmental impacts.

Abstract Flexible endoscopic evaluation of swallowing (FEES) is one of the most important methods for instrumental swallowing evaluation. The most challenging part of the examination consists in the interpretation of the various observations encountered during endoscopy and in the deduction of clinical consequences. This review proposes the framework for an integrated FEES-report that systematically moves from salient findings of FEES to more advanced domains such as dysphagia severity, phenotypes of swallowing impairment and pathomechanisms. Validated scales and scores are used to enhance the diagnostic yield. In the concluding part of the report, FEES-findings are put into the perspective of the clinical context. The potential etiology of dysphagia and conceivable differential diagnoses are considered, further diagnostic steps are proposed, treatment options are evaluated, and a timeframe for re-assessment is suggested. This framework is designed to be adaptable and open to continuous evolution. Additional items, such as novel FEES protocols, pathophysiological observations, advancements in disease-related knowledge, and new treatment options, can be easily incorporated. Moreover, there is potential for customizing this approach to report on FEES in structural dysphagia.

Fast scanning chip calorimetry (FSC) allows subjecting polymer melts to well-defined vitrification, crystal nucleation, and crystal growth pathways and, therefore, precise control of morphologies, from fully amorphous glassy states to semicrystalline structures containing perfect crystals. Due to the required use of nanogram-sized samples, needed to achieve high cooling rates, their mechanical properties, in order to establish structure-property relations, are difficult to assess. In this work, indentation modulus and indentation hardness of FSC samples are successfully determined on example of semicrystalline poly (ʟ-lactic acid) (PLLA) containing spherulitically grown disorder α′- or rather perfect α-crystals, with the correctness of the applied preparation and analyses routes confirmed by nanoindentation measurements on milligram-sized samples prepared through hotstage microscopy, and by applying both static single-step and quasi-continuous stiffness measurements. Modulus and hardness data are consistent with prior analyses of bulk samples, confirming that semicrystalline PLLA containing α-crystals exhibits around 10–20 % higher values of these properties compared to PLLA containing α′-crystals, related to the different molecular-chain packing in the crystal lattice. This work demonstrates that combination of FSC and nanoindentation techniques is an effective tool for determining mechanical properties of samples solidified at specific thermal pathways which otherwise cannot be realized.

Summary: In South Tyrol (Eastern Italian Alps), during Late Antiquity-Early Middle Ages, archeological records indicate cultural hybridization among alpine groups and peoples of various origin. Using paleogenomics, we reconstructed the ancestry of 20 individuals (4th–7th cent. AD) from a cemetery to analyze whether they had heterogeneous or homogeneous ancestry and to study their social organization. The results revealed a primary genetic ancestry from southern Europe and additional ancestries from south-western, western, and northern Europe, suggesting that cultural hybridization was accompanied by complex genetic admixture. Kinship analyses found no genetic relatedness between the only two individuals buried with grave goods. Instead, a father-son pair was discovered in one multiple grave, together with unrelated individuals and one possible non-local female. These genetic findings indicate the presence of a high social status familia, which is supported by the cultural materials and the proximity of the grave to the most sacred area of the church.

Abstract Background In 1975, the mummified body of a female has been found in the Franciscan church in Basel, Switzerland. Molecular and genealogic analyses unveiled her identity as Anna Catharina Bischoff (ACB), a member of the upper class of post-reformed Basel, who died at the age of 68 years, in 1787. The reason behind her death is still a mystery, especially that toxicological analyses revealed high levels of mercury, a common treatment against infections at that time, in different body organs. The computed tomography (CT) and histological analysis showed bone lesions in the femurs, the rib cage, and the skull, which refers to a potential syphilis case. Results Although we could not detect any molecular signs of the syphilis-causing pathogen Treponema pallidum subsp. pallidum, we realized high prevalence of a nontuberculous mycobacterium (NTM) species in brain tissue sample. The genome analysis of this NTM displayed richness of virulence genes and toxins, and similarity to other infectious NTM, known to infect immunocompromised patients. In addition, it displayed potential resistance to mercury compounds, which might indicate a selective advantage against the applied treatment. This suggests that ACB might have suffered from an atypical mycobacteriosis during her life, which could explain the mummy’s bone lesion and high mercury concentrations. Conclusions The study of this mummy exemplifies the importance of employing differential diagnostic approaches in paleopathological analysis, by combining classical anthropological, radiological, histological, and toxicological observations with molecular analysis. It represents a proof-of-concept for the discovery of not-yet-described ancient pathogens in well-preserved specimens, using de novo metagenomic assembly.

Background: Several computed tomographic studies have shown the presence of atherosclerosis in ancient human remains. However, while it is important to understand the development of atherosclerotic cardiovascular disease (ASCVD), genetic data concerning the prevalence of the disease-associated single nucleotide polymorphisms (SNPs) in our ancestors are scarce. Objective: For a better understanding of the role of genetics in the evolution of ASCVD, we applied an enrichment capture sequencing approach to mummified human remains from different geographic regions and time periods. Methods: Twenty-two mummified individuals were analyzed for their genetic predisposition of ASCVD. Next-generation sequencing methods were applied to ancient DNA (aDNA) samples, including a novel enrichment approach specifically designed to capture SNPs associated with ASCVD in genome-wide association studies of modern humans. Findings: Five out of 22 ancient individuals passed all filter steps for calculating a weighted polygenic risk score (PRS) based on 87 SNPs in 56 genes. PRSs were correlated to scores obtained from contemporary people from around the world and cover their complete range. The genetic results of the ancient individuals reflect their phenotypic results, given that the only two mummies showing calcified atherosclerotic arterial plaques on computed tomography scans are the ones exhibiting the highest calculated PRSs. Conclusions: These data show that alleles associated with ASCVD have been widespread for at least 5,000 years. Despite some limitations due to the nature of aDNA, our approach has the potential to lead to a better understanding of the interaction between environmental and genetic influences on the development of ASCVD.

Based on the assumption that social media encourages a populist style of politics in online communities and the proposition that populism and conspiracy theories tend to co-occur, this article investigates whether this holds true for YouTube influencers, particularly on the less investigated left-wing spectrum. The article provides qualitative case studies of four different groups of political content creators on YouTube whose content makes use of or analyzes popular culture. The article concludes that a populist style plays a far less central role in left-wing communities on YouTube than on other platforms or within right-wing communities.

Three-hundred-and-thirty-four cognitive profiles from neuropsychological examinations assessed during a 5-year period (2015 to 2020) from geriatric patients of a day clinic in the south of Germany were analyzed. For this purpose, the profiles were divided into the following subgroups: (1) Mild Cognitive Impairment, no depression (2) Onset or mild dementia, no depression (3) No cognitive deficit, depression (4) cognitively impaired (MCI, dementia) and depression. Subgroups were be compared using analysis of variance (independent variable IV: diagnostic groups, dependent variable DV: cognitive functions) to reveal specific differences that will allow a differential diagnosis. Post-hoc comparisons and a graphical representation of the cognitive profiles were also investigated. All cognitive profiles with a Mini-Mental-State-Examination (MMSE) score of 25 or more points were selected for analysis if they had complete data from the following testing procedures: MMSE, clock drawing test, Geriatric Depression Scale (GDS), Syndrom-Kurztest (SKT), Nuremberg Aging Inventory (NAI) maze test, Wechsler Adult Intelligence Scale (WAIS) similarities, Rivermead Behavioral Memory Test (RBMT) story immediate and delayed. The results will help to improve the differential diagnostic examination of older depressed people with and without cognitive impairment: Depressed patients usually have no objectifiable memory impairment and inconspicuous scores in the logical structure of thought processes, while attention was usually impaired in both depressed and demented patients.

An unprecedented number of memes emerged in response to the 2020 U.S. presidential elections. This article offers a thematic analysis of a corpus of memes published on Twitter between November 3, 2020 and January 20 2021 in relation to the U.S. presidential election. By further employing a qualitative discourse analysis and close readings of selected examples, this article explores the stances and intertextual references expressed in the memetic discourse. I illustrate which events users engage with, how they frame them using the elements of American pop culture, and the different functions such memes served for different publics. Central events – such as Donald Trump’s press conference in a Four Seasons Total Landscaping parking lot, Joe Biden’s victory and rumors about the Russian president Putin resigning – were commented upon both with broad references to widely popular franchises such as Star Wars and with multi-layered intertextual references to iconography of meme culture such as the Hockey mascot Gritty. Memes exaggerated events for comedic purposes, providing relief after a long time of tension, as well as possibly trivializing and distorting public perception of events. While meme activity peaked on November 6th and 7th, a singular viral meme of Bernie Sanders emerged after Joe Biden’s inauguration, illustrating a different genre of meme as a response to a different political situation in which the political figure serves a wide variety of purposes in commenting upon popular culture. Such memes served to establish a sense of community, agency, and catharsis after the anxieties many Democratic voters experienced prior to the election. These findings present the growing role of popular and fan culture to political discourse on mainstream social media platforms and their varied and highly flexible expression.

An approach for life-cycle-based sustainability assessment for innovative energy technologies was developed that includes Life Cycle Assessment, economic assessment and selected social indicators, i.e. acceptance, patents and added value. As a case study for this approach, hydrogen supply by wind powered electrolysis was assessed and different distribution options to its final use in fuel cell vehicles were compared. First results of the Life Cycle Assessment show that lowest environmental impacts are caused by transporting hydrogen in pipelines, which is also the most cost-effective option. The preliminary survey about hydrogen refuelling stations showed that the fear of explosions is most relevant to people. Regarding added value, it could be revealed that a slight shift from domestic to more globalised expenditures is to be expected in the future. It can be concluded that hydrogen supply by pipelines is the most sustainable option. However, for the implementation of this technology, social issues such as acceptance of hydrogen filling stations and decrease of local employment have to be addressed.

Abstract A duplex treatment consisting of plasma nitriding (PN) and physical vapor deposition (PVD) significantly improves the thermal, tribological, and corrosion resistance of forming tools, and especially if they are intended for applications subject to high mechanical loads. This study investigates the influence of nitriding on the properties of a conventionally heat‐treated AISI D2 tool steel, coated with a Cr‐Al‐Ti‐B‐N layer, while the effect of the presence or absence of a compound layer is discussed. PN is performed at 510–520°C using different N2‐H2 gas mixtures. The Cr‐Al‐Ti‐B‐N layers are deposited at 480°C using a combination of cathodic arc evaporation and magnetron sputtering. The samples are characterized using electron probe microanalysis with wavelength‐dispersive X‐ray spectroscopy, optical and scanning electron microscopy, glancing‐angle X‐ray diffraction, surface hardness measurements, profilometry, Rockwell indentation, and scratch tests. These techniques reveal relationships between the depth gradient of the chemical composition and microstructure of the nitrided interlayer, the adhesion of the PVD coating, and the hardness of the tool steel. Although the PVD process induces a structural transformation in the compound layer, this transition does not have a negative influence on the adhesion of the PVD coating.

Abstract The stability of an iron nitride compound layer prepared by plasma nitriding of AISI D2 tool steel is investigated using in situ high‐temperature X‐ray diffraction at rising temperature up to 470°C and for an isothermal treatment at 450°C. Both kinds of experiment were carried out in vacuum. For all treatments, the iron nitride compound layer, which consists mainly of ε‐Fe3N, decomposes and forms an α‐Fe ‘black’ layer. The stability of the iron nitride compound layer is discussed in terms of the phase composition, the relative change of the lattice parameter, the nitrogen content and the decomposition kinetic. The decomposition takes place via a phase transition in two steps: (i) the out‐diffusion of nitrogen from ε‐Fe3N above an annealing temperature of 300°C and (ii) the transformation of ε‐Fe3Ny into α‐Fe when the nitrogen content (y) declines below 0.66. The second step is accompanied by the formation of Fe3C precipitates at about 450°C.

Predictive coding models of brain processing propose that top-down cortical signals promote efficient neural signaling by carrying predictions about incoming sensory information. These “priors” serve to constrain bottom-up signal propagation where prediction errors are carried via feedforward mechanisms. Depression, traditionally viewed as a disorder characterized by negative cognitive biases, is associated with disrupted reward prediction error encoding and signaling. Accumulating evidence also suggests that depression is characterized by impaired local and long-range prediction signaling across multiple sensory domains. This review highlights the electrophysiological and neuroimaging evidence for disrupted predictive processing in depression. The discussion is framed around the manner in which disrupted generative predictions about the sensorium could lead to depressive symptomatology, including anhedonia and negative bias. In particular, the review focuses on studies of sensory deviance detection and reward processing, highlighting research evidence for both disrupted generative predictions and prediction error signaling in depression. The role of the monoaminergic and glutamatergic systems in predictive coding processes is also discussed. This review provides a novel framework for understanding depression using predictive coding principles and establishes a foundational roadmap for potential future research.

Background: Many digital health technologies capable of atrial fibrillation (AF) detection are directly available to patients. However, adaptation into clinical practice by heart rhythm healthcare practitioners (HCPs) is unclear. Objective: To examine HCP perspectives on use of commercial technologies for AF detection and management. Methods: We created an electronic survey for HCPs assessing practice demographics and perspectives on digital devices for AF detection and management. The survey was distributed electronically to all members of 3 heart rhythm professional societies. Results: We received 1601 responses out of 73,563 e-mails sent, with 43.6% from cardiac electrophysiologists, 12.8% from fellows, and 11.6% from advanced practice practitioners. Most respondents (62.3%) reported having recommended patient use of a digital device for AF detection. Those who did not had concerns about their accuracy (29.6%), clinical utility of results (22.8%), and integration into electronic health records (19.8%). Results from a 30-second single-lead electrocardiogram were sufficient for 42.7% of HCPs to recommend oral anticoagulation for patients at high risk for stroke. Respondents wanted more data comparing the accuracy of digital devices to conventional devices for AF monitoring (64.9%). A quarter (27.3%) of HCPs had no reservations recommending digital devices for AF detection, and most (53.4%) wanted guidelines from their professional societies providing guidance on their optimal use. Conclusion: Many HCPs have already integrated digital devices into their clinical practice. However, HCPs reported facing challenges when using digital technologies for AF detection, and professional society recommendations on their use are needed.

Rapid-acting interventions for the suicide crisis have the potential to transform treatment. In addition, recent innovations in suicide research methods may similarly expand our understanding of the psychological and neurobiological correlates of suicidal thoughts and behaviors. This review discusses the limitations and challenges associated with current methods of suicide risk assessment and presents new techniques currently being developed to measure rapid changes in suicidal thoughts and behavior. These novel assessment strategies include ecological momentary assessment, digital phenotyping, cognitive and implicit bias metrics, and neuroimaging paradigms and analysis methodologies to identify neural circuits associated with suicide risk. This review is intended to both describe the current state of our ability to assess rapid changes in suicide risk as well as to explore future directions for clinical, neurobiological, and computational markers research in suicide-focused clinical trials.

At the heart of most Power-to-X (PtX) concepts is the utilization of renewable electricity to produce hydrogen through the electrolysis of water. This hydrogen can be used directly as a final energy carrier or it can be converted into, for example, methane, synthesis gas, liquid fuels, electricity, or chemicals. Technical demonstration and systems integration are of major importance for integrating PtX into energy systems. As of June 2020, a total of 220 PtX research and demonstration projects in Europe have either been realized, completed, or are currently being planned. The central aim of this review is to identify and assess relevant projects in terms of their year of commissioning, location, electricity and carbon dioxide sources, applied technologies for electrolysis, capacity, type of hydrogen post-processing, and the targeted field of application. The latter aspect has changed over the years. At first, the targeted field of application was fuel production, for example for hydrogen buses, combined heat and power generation, and subsequent injection into the natural gas grid. Today, alongside fuel production, industrial applications are also important. Synthetic gaseous fuels are the focus of fuel production, while liquid fuel production is severely under-represented. Solid oxide electrolyzer cells (SOECs) represent a very small proportion of projects compared to polymer electrolyte membranes (PEMs) and alkaline electrolyzers. This is also reflected by the difference in installed capacities. While alkaline electrolyzers are installed with capacities between 50 and 5000 kW (2019/20) and PEM electrolyzers between 100 and 6000 kW, SOECs have a capacity of 150 kW. France and Germany are undertaking the biggest efforts to develop PtX technologies compared to other European countries. On the whole, however, activities have progressed at a considerably faster rate than had been predicted just a couple of years ago.

Green hydrogen for mobility represents an alternative to conventional fuel to decarbonize the transportation sector. Nevertheless, the thermodynamic properties make the transport and the storage of this energy carrier at standard conditions inefficient. Therefore, this study deploys a georeferenced optimal transport infrastructure for four base case scenarios in France and Germany that differs by production distribution based on wind power potential and demand capacities for the mobility sector at different penetration shares for 2030 and 2050. The restrained transport network to the road infrastructure allows focusing on the optimum combination of trucks operating at different states of aggregations and storage technologies and its impact on the annual cost and hydrogen flow using linear programming. Furthermore, four other scenarios with production cost investigate the impact of upstream supply chain cost, and eight scenarios with daily transport and storage optimization analyse the modeling method sensitivity. The results show that compressed hydrogen gas at a high presser level around 500 bar was, on average, a better option. However, at an early stage of hydrogen fuel penetration, substituting compressed gas at low to medium pressure levels by liquid organic hydrogen carrier minimizes the transport and storage costs. Finally, in France, hydrogen production matches population distribution, in contrast to Germany, which suffers from supply and demand disparity.

Penelitian bertujuan untuk mendeskripsikan nilai-nilai budaya dan menganalisis cara masyarakat masyarakat etnis Tionghoa di Desa Sewan Kota Tangerang mensosialisasikan nilai-nilai budaya itu kepada generasi berikutnya dan strategi transformasi nilai-nilai budaya masyarakat etnis Tionghoa sebagai sumber pembelajaran Ilmu Pengetahuan Sosial. Adapun pendekatan dalam penelitian ini adalah pendekatan kualitatif, dengan menggunakan metode studi kasus (case study). Teknik pengumpulan data yang dipergunakan adalah wawancara, observasi, studi dokumentasi dan triangulasi. Teknik validasi data menggunakan member-check, triangulasi dan expert opinion. Hasil penelitian ini menunjukkan bahwa (1) Nilai-nilai budaya yang sangat menonjol pada masyarakat etnis Tionghoa adalah nilai-nilai wirausaha. Ada lima karakteristik para pelaku wirausaha etnis Tionghoa di desa Sewan adalah: ciri percaya diri, berorientasikan tugas dan hasil, pengambil resiko, orisinalitas, berorientasi ke masa depan. Nilai budaya yang menonjol berikutnya adalah ketaatan terhadap tradisi atau adat istiadat (2) Proses sosialisasi nilai-nilai budaya masyarakat etnis Tionghoa di desa Sewan Kota Tangerang kepada generasi berikutnya melalui proses dengan tahap-tahap sebagai berikut: pertama, melalui fase pembentukan kebiasaan (habit forming). Kedua, fase pembentukan (formatif). Ketiga, fase embryonic. Keempat, fase productive. Fase terakhir adalah fase kemapanan / fase kematangan (maturation). (3) Nilai-nilai budaya masyarakat etnis Tionghoa di desa Sewan tersebut sangat memungkinkan ditransformasikan ke dalam pembelajaran Ilmu Pengetahuan Sosial (IPS) di sekolah, terutama di tingkat Sekolah Menengah Pertama (SMP), melalui pembelajaran kontekstual.

Metastable phases are often used to design materials with outstanding properties, which cannot be achieved with thermodynamically stable compounds. In many cases, the metastable phases are employed as precursors for controlled formation of nanocomposites. This contribution shows how the microstructure of crystalline metastable phases and the formation of nanocomposites can be concluded from X-ray diffraction experiments by taking advantage of the high sensitivity of X-ray diffraction to macroscopic and microscopic lattice deformations and to the dependence of the lattice deformations on the crystallographic direction. The lattice deformations were determined from the positions and from the widths of the diffraction lines, the dependence of the lattice deformations on the crystallographic direction from the anisotropy of the line shift and the line broadening. As an example of the metastable system, the supersaturated solid solution of titanium nitride and aluminium nitride was investigated, which was prepared in the form of thin films by using cathodic arc evaporation of titanium and aluminium in a nitrogen atmosphere. The microstructure of the (Ti,Al)N samples under study was tailored by modifying the [Al]/[Ti] ratio in the thin films and the surface mobility of the deposited species.

Industrial hydrogen production via alkaline water electrolysis (AEL) is a mature hydrogen production method. One argument in favor of AEL when supplied with renewable energy is its environmental superiority against conventional fossil-based hydrogen production. However, today electricity from the national grid is widely utilized for industrial applications of AEL. Also, the ban on asbestos membranes led to a change in performance patterns, making a detailed assessment necessary. This study presents a comparative Life Cycle Assessment (LCA) using the GaBi software (version 6.115, thinkstep, Leinfelden-Echterdingen, Germany), revealing inventory data and environmental impacts for industrial hydrogen production by latest AELs (6 MW, Zirfon membranes) in three different countries (Austria, Germany and Spain) with corresponding grid mixes. The results confirm the dependence of most environmental effects from the operation phase and specifically the site-dependent electricity mix. Construction of system components and the replacement of cell stacks make a minor contribution. At present, considering the three countries, AEL can be operated in the most environmentally friendly fashion in Austria. Concerning the construction of AEL plants the materials nickel and polytetrafluoroethylene in particular, used for cell manufacturing, revealed significant contributions to the environmental burden.