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Laura Kulik,1 Leonardo G da Fonseca,2 Aiwu Ruth He,3 Jordi Rimola,4 Andrea Wilson Woods,5 York F Zöllner,6 Peter R Galle7 1Northwestern University, Chicago, IL, USA; 2Clinical Oncology, Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil; 3Georgetown University, Washington, DC, USA; 4Radiology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain; 5Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, AL, USA; 6Hamburg University of Applied Sciences, Competence Center Health, Hamburg, Germany; 7University Medical Centre Mainz, Mainz, GermanyCorrespondence: Peter R GalleUniversity Medical Centre Mainz, Mainz, GermanyTel +49 6131 177275Email Peter.Galle@unimedizin-mainz.deAbstract: A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.Keywords: hepatocellular carcinoma, immuno-oncologics, biomarkers, patient-reported outcomes

Sebastian Bernuth,1 Daniel Grimm,1 Johanna Vollmar,1 Felix Darstein,1 Jens Mittler,2 Michael Heise,2 Maria Hoppe-Lotichius,2 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann1 1First Department of Internal Medicine, Transplant Hepatology, 2General-, Abdominal- and Transplant- Surgery, University Medical Center, Johannes Gutenberg University, Mainz, Germany Background: Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) has been a frequent and relevant problem in the past two decades. This analysis evaluated the efficacy and safety of new interferon (IFN)-free direct-acting antiviral (DAA) therapies in a large real-world cohort of HCV patients after LT.Methods: We retrospectively analyzed a cohort of 157 patients infected with HCV who underwent deceased donor LT between 1997 and 2014. Patient survival, outcome, and side effects of antiviral therapy were assessed.Results: Survival with recurrent HCV genotype 1 (GT1) infection was inferior to other HCV GTs (P=0.01). The overall sustained virological response (SVR) rate with new DAA therapy was 94.6% (n=37). Patients with both GT1 and other GTs reached SVR rates >90%. We noticed a few side effects, mainly caused by ribavirin, and only one discontinuation in DAA-treated patients.Conclusion: DAA therapy was effective and safe in previous hard-to-treat patients after LT in this real-world cohort. Keywords: HCV, DAA, liver transplantation, reinfection, sustained virological response, SVR

O estudo investiga a compatibilidade do dano existencial com o Direito brasileiro. Delimita a abordagem em três frentes: (i) investiga o dano existencial no Direito italiano, (ii) descreve como o dano existencial foi incorporado no Direito brasileiro e, com isso, (iii) faz uma avaliação crítica da recepção deste instituto jurídico. Procura, assim, apresentar as características do dano existencial no Direito italiano e faz um escrutínio sobre a (in)adequada recepção no Direito brasileiro. A hipótese do estudo é de que a recepção dos danos existenciais, no Brasil, pode ser feita, de maneira juridicamente adequada, observando alguns parâmetros e retificações específicas. Fez-se o uso de revisão bibliográfica e análise empírica de julgamentos.

Abstract Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age.

Abstract People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p

Background: It is widely recommended for teachers to provide positive feedback to foster the development and maintenance of children's motivation and perseverance. However, not all positive feedback has positive consequences and an important differentiation can be made between positive person-oriented feedback (i.e. 'you are very talented') and process-oriented feedback (i.e. 'you showed great perseverance'). Specific evidence- and theory-based recommendations regarding the impact of different types of positive feedback will benefit children's experiences in physical education and sports. Purpose: The present study addressed this topic by carrying out an experimental study on the provision of different types of positive feedback on children's perseverance following failure experience in motor tasks. Since it has been suggested that children's ability as well as their degree of insecurity or self-esteem may affect how they respond to different types of feedback, we also consider the role of individual differences between children. Specifically, it was examined whether the impact of the different types of feedback depends on children's actual and perceived motor competence and narcissism levels. Methods: A sample of 176 Flemish children (44.3% boys, 9-13 years) received either person-oriented, process-oriented or neutral positive feedback after a set of easy motor tasks in which they succeeded. Next, children engaged in motor tasks that were too difficult for their age so that they had a failure experiences after which they received negative feedback. Children's perseverance following failure was measured by monitoring at which difficulty level and how long they kept on practicing. Prior to the experiment, children's level of actual and perceived motor competence and narcissism was measured. Results: Children who received process-oriented positive feedback chose more difficult exercises than children in the neutral positive feedback condition. Children in the process-oriented feedback condition also persisted longer than children in the person-oriented positive feedback and control condition. These effects were independent of both children's level of actual and perceived motor competence and narcissism. Conclusion: This study shows that not all forms of positive feedback are equally effective to increase perseverance. The results highlight the importance of offering process-oriented rather than person-oriented positive feedback to increase children's perseverance when facing difficult tasks.

Johanna Vollmar,1 Maren Christina Bellmann,1 Felix Darstein,1 Maria Hoppe-Lotichius,2 Jens Mittler,2 Michael Heise,2 Bernd Rüttger,3 Veronika Weyer,4 Anca Zimmermann,5 Hauke Lang,2 Peter R Galle,1 Tim Zimmermann1 1First Department of Internal Medicine, Gastroenterology and Hepatology, Johannes Gutenberg University, Mainz, Germany; 2Department of Hepatobiliary and Transplantation Surgery, Johannes Gutenberg University, Mainz, Germany; 3Panacea Biotec Germany GmbH, Munich, Germany; 4Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; 5First Department of Internal Medicine, Endocrinology and Metabolic Diseases, Johannes Gutenberg University, Mainz, Germany Background: Expensive pharmaceuticals are a major reason for cost intensive health care systems. Long-term immunosuppressive therapy plays a relevant role after organ transplantation. Patents of original drugs have expired and cheaper products are available. Little data are available regarding efficacy and safety of generic immunosuppressive agents.Methods: In this prospective study, 25 patients, who were clinically stable for a minimum of 2 years after liver transplantation, were converted from the original formulations of tacrolimus (TAC) and mycophenolate mofetil to the generics Tacpan® (TAP) and Mowel® (MOW). Patients were followed-up for 6 months. Results were compared retrospectively to 25 age- and sex-matched controls treated with the original brands.Results: In the matched-pair analysis of TAC trough level/dose ratio, no significant difference was found between TAP/MOW and TAC/mycophenolate mofetil groups. No acute rejection occurred in either group. In total, 17 patients reported mild side effects in the TAP/MOW group. The most common side effects were gastrointestinal symptoms. Intra-individual analysis of costs revealed a considerable cost reduction in the TAP/MOW group (in median 25.03%; P

Johanna Knapstein,1 Daniel Grimm,1 Marcus A Wörns,1 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann111st Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany; 2Department of General, Visceral and Transplantation Surgery, Johannes Gutenberg-University, Mainz, GermanyIntroduction: Hepatitis C virus (HCV) reinfection occurs universally after liver transplantation, with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Dual antiviral therapy with pegylated interferon-2a (peg-IFN) and ribavirin (RBV) only reaches sustained virological response rates of ~30% after liver transplantation. With the approval of viral NS3/4A protease inhibitors telaprevir (TVR), boceprevir, and simeprevir and the NS5B polymerase inhibitor sofosbuvir, combination therapy offers new therapeutic options for HCV-infected patients, resulting in considerably higher sustained virological response rates in the nontransplant setting. Case presentation: We report three cases of TVR-based triple antiviral therapy in HCV genotype 1 reinfected patients after liver transplantation, of whom a 57-year-old Caucasian female and a 43-year-old Caucasian male were therapy naïve, and a 49-year-old Caucasian male patient was pretreated ineffectively. After 4 weeks of therapy, viral load decreased one to three log10 and became negative in weeks 6 to 8 in the therapy naïve patients. The pretreated patient showed a negative viral load in week 4. TVR was administered over 12 weeks, 750 mg thrice daily. Doses of immunosuppression with cyclosporine were reduced four to six fold. Initial peg-IFN and RBV doses ranged from 135–180 µg/week and 800–1,200 mg/day, according to the patient's body weight. Doses of peg-IFN and RBV were adapted to 90–135 µg/week and 400–800 mg/day after 2 to 12 weeks of protease inhibitor therapy. Dual therapy was continued for 36 weeks with total treatment duration of 48 weeks in the therapy naïve patients leading to a sustained virological response 12 weeks after the end of therapy. In the pretreated patient a breakthrough was detected in week 24 and therapy was discontinued. Overall, antiviral therapy was well tolerated. Side effects included dysgeusia and anemia leading to erythropoietin application and blood transfusions. Conclusion: This case series emphasizes that triple therapy with TVR is an efficient treatment for therapy naïve HCV genotype 1 reinfected patients after liver transplantation. But therapeutic options for pretreated patients require improvement. Keyword: cyclosporine, interferon, ribavirin, hepatitis C, protease inhibitor

Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear. Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics. Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p

No presente estudo, buscou-se responder a pergunta: como a participação de professores em um espaço formativo que proporciona aprimoramento didático/metodológico pode ampliar suas concepções da pesquisa como princípio educativo? Trata-se de uma investigação com abordagem qualitativa do tipo exploratória. Os participantes foram 10 professores de um curso de formação continuada, e as informações foram produzidas a partir de um questionário on-line, sendo analisadas por meio da Análise Textual Discursiva. Da análise das informações, emergiram três categorias: (i) ampliação da compreensão sobre a pesquisa; (ii) valorização das perguntas dos estudantes na sala de aula, (iii) mobilização do envolvimento de estudantes no processo de investigação no contexto de sala de aula. Há indicativos da potencialidade de formações que, de modo teórico e prático, abordem a pesquisa como princípio educativo e como forma de possibilitar a reflexão do professor acerca da pesquisa enquanto modo amplo de ensinar e aprender.

Abstract Background and Aims East African countries have high rates of maternal and child mortality and morbidity. Studies have shown that the involvement of male partners in reproductive health can benefit maternal and child health (MCH). This scoping review aims to provide an overview of the evidence across East Africa that describes male partner involvement and its effect on maternal, reproductive, and child well‐being. Methods Ten databases were searched to identify quantitative data on male's involvement in East Africa. Studies reporting qualitative data, “intention to use” data or only reporting on male partner's education or economic status were excluded. Studies were organized into five a priori categories: antenatal care (ANC), human immunodeficiency virus, breastfeeding, family planning, and intimate partner violence with further categories developed based on studies included. Results A total of 2787 records were identified; 644 full texts were reviewed, and 96 studies were included in this review. Data were reported on 118,967 mothers/pregnant women and 15,361 male partners. Most of the studies (n = 83) were reported from four countries Ethiopia (n = 49), Kenya (n = 14), Tanzania (n = 12) and Uganda (n = 10). The evidence indicates that male partner involvement and support is associated with improved reproductive, MCH across a wide range of outcomes. However, the studies were heterogeneous, using diverse exposure and outcome measures. Also, male partners' lack of practical and emotional support, and engagement in violent behaviors towards partners, were associated with profound negative impacts on MCH and well‐being. Conclusions The body of evidence, although heterogeneous, provides compelling support for male involvement in reproductive health programs designed to support MCH. To advance research in this field, an agreement is needed on a measure of male partner “involvement.” To optimize benefits of male partners' involvement, developing core outcome sets and regional coordination are recommended.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Background & Aims: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE). Methods: Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation. Results: A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication. Conclusions: PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication. Impact and implications: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) vs sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety in patient subpopulations with Vp4 portal vein tumor thrombosis (PVTT) and other high-risk prognostic factors are reported. Methods: IMbrave150 was a global, randomized (2:1), open-label, phase 3 study in systemic treatment–naive patients with unresectable HCC; OS and PFS were co-primary endpoints. Exploratory analyses compared the efficacy and safety of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks vs sorafenib 400 mg twice daily in patients (i) with and without Vp4 PVTT alone and (ii) with and without high-risk prognostic factors. Results: In patients with Vp4 PVTT, median OS was 7.6 months (95% CI 6.0-13.9) with atezolizumab plus bevacizumab (n=48) and 5.5 months (95% CI 3.4-6.7) with sorafenib (n=25; HR 0.62 [95% CI 0.34-1.11]; descriptive P=0.104). Median PFS in the respective arms was 5.4 months (95% CI 3.6-6.9) and 2.8 months (95% CI 1.5-5.3; HR 0.62 [95% CI 0.35-1.09]; descriptive P=0.094). In patients without Vp4, median OS was 21.1 months (95% CI 18.0-24.6) with atezolizumab plus bevacizumab (n=288) and 15.4 months (95% CI 12.6-18.6) with sorafenib (n=140; HR 0.67 [95% CI 0.51-0.88]; descriptive P=0.003). Median PFS in the respective arms was 7.1 months (95% CI 6.1-9.6) and 4.7 months (95% CI 4.2-6.1; HR 0.64 [95% CI 0.51-0.81]; descriptive P

Reuse of entire insulating glas units (IGUs) in façades is a high-level circular strategy to decrease material and energy use and CO2 emissions. Yet, how many post-consumer IGUs are fit for such a direct reapplication and comply to building regulations having a 90% nominal argon filling and a sufficient residual lifetime? To address this question, almost one thousand IGUs in more than 40 different buildings in The Netherlands were studied. The glass and cavity width and the argon concentration were measured with the Sparklike Laser Portable. Then, each IGU was double-checked with a standalone glass thickness meter to verify non-standard cavity widths. The product age was obtained via the spacer code or general building information. A threshold of maximum 15 years was set as general indicator of a residual service life of 10 to 25 years. The results of the applied method show that just over 50% of the IGUs meet the required argon concentration. Furthermore, the combination of a maximum IGU product age of 15 years and a 90% nominal argon fill resulted in 24% of tested IGUs as potentially suitable for reuse. The results raise questions about the reuse of IGUs in practice, which are discussed in this paper.

In this paper we have tried, starting from the results of an analysis of the functioning of integrated care in the Belgian Health System by Martens et al, to design a strategy that could contribute to better addressing the challenges of the 21st century in Belgium. We proposed health system changes at the macro-, meso- and micro-level. We focused on health policy development and organization of care, emphasizing the importance of a shift from a hospital-centric towards a primary care based approach. Special attention was paid to the need for institutional reforms, in order to facilitate the further development of interprofessional integrated care, that focuses on the achievement of the life-goals of a person.

Abstract Background Spleen stiffness measurement (SSM) performed by transient elastography at 100 Hz is a novel technology for the evaluation of portal hypertension in advanced chronic liver disease, but technical aspects are lacking. We aimed to evaluate the intraexamination variability of SSM and to determine the best transient elastography protocol for obtaining robust measurements to be used in clinical practice. Methods We analyzed 253 SSM exams with up to 20 scans for each examination, performed between April 2021 and June 2022. All SSM results were evaluated according to different protocols by dividing data into groups of n measurements (from 2 to 19). Considering as reference the median SSM values across all the 20 measurements, we calculated the distribution of the absolute deviations of each protocol from the reference median. This analysis was repeated 1,000 times by resampling the data. Distributions were also stratified by etiology (chronic liver disease versus clinically significant portal hypertension) and different SSM ranges: 75 kPa. Results Overall, we observed that the spleen stiffness exam had less variability if it exceeded 12 measurements, i.e., absolute deviations ≤ 5 kPa at 95% confidence. For exams with higher SSM values (> 75 kPa), as seen in clinically significant portal hypertension, at least 15 measurements are highly recommendable. Conclusions Fifteen scans per examination should be considered for each SSM exam performed at 100 Hz to achieve a low intraexamination variability within a reasonable time in clinical practice. Relevance statement Performing at least 15 scans per examination is recommended for 100 Hz SSM in order to achieve a low intraexamination variability, in particular for values > 75 kPa compatible with clinically significant portal hypertension. Key points • Spleen stiffness measurement by transient elastography is used for stratification in patients with portal hypertension. • At 100 Hz, this method may have intraexamination variability. • A minimum of 15 scans per examination achieves a low intraexamination variability. Graphical Abstract

This study's purpose was to explore the relationship between emotional intelligence (EI) and motor competence (MC) in 540 children, adolescents, and young adults. Using the Schutte Self-Report Emotional Intelligence Scale (SSEIT), participants were divided in three groups of high, average, and low EI. The short form of Bruininks-Oseretsky Test for Motor Proficiency -- 2 (BOTMP-2SF) evaluated MC. Within each age and sex group, associations between MC and a) EI as a global construct and b) the four subdomains of EI were overall significant (with p < 0.01 for 85 out of 90 correlations) and very strong (with 66 correlations > 0.60). A 3 (EI groups) x 3 (age groups) x 2 (sex) ANOVA on standardized overall MC scores revealed that in all age groups, participants with higher EI outperformed their peers with average and low EI with respect to MC (p < 0.001). Additionally, boys scored higher on MC tests compared to girls (p < 0.001). A third-order interaction effect (p < 0.001) revealed that boys' superiority in MC generally decreased from childhood to adulthood, especially in the low EI group. The outcomes of this study show a robust relationship between EI and MC from childhood through early adulthood, suggesting a novel MC correlate throughout the lifespan.

Sports, with their various social manifestations, exhibit racist structures and incidents. Physical education (PE) has the potential to serve as an environment to combat racism, but it can also perpetuate and (re)produce racist attitudes and behaviors. This study aimed to conduct a systematic review of national (German) and international literature concerning racism and anti-racism within the context of PE specifically from a students’ perspective. The research methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard and encompassed a four-step process: (1) searching 11 electronic databases using 70 keyword combinations in both German and English; (2) selecting studies based on five predetermined inclusion criteria; (3) evaluating the quality of selected studies using established appraisal tools; and (4) conducting descriptive and template analyses. Of 5,213 publications, 16 met the inclusion criteria, demonstrating diverse theoretical frameworks and methodological approaches. Five themes were constructed: “How racism is understood” (1); “What students experience,” encompassing discriminatory incidents in PE, sports, and daily life classified as racial stereotypes, prejudices, and everyday racism (2); and “What physical education teachers (3)/Institutions (4)/researchers (5) can and should do.” These themes provided recommendations for teachers, institutions, and researchers, including training and curriculum reforms. While valuable international literature was identified, no German PE specific publications were found emphasizing the necessity of a local (German) survey to comprehend students’ experiences, knowledge, and potential for anti-racism efforts. Such insights are crucial for shaping teacher-related training programs and policy demands in an informed and targeted manner.

Objectives: We have previously shown that lactate is an essential metabolite for macrophage polarisation during ischemia-induced muscle regeneration. Recent in vitro work has implicated histone lactylation, a direct derivative of lactate, in macrophage polarisation. Here, we explore the in vivo relevance of histone lactylation for macrophage polarisation after muscle injury. Methods: To evaluate macrophage dynamics during muscle regeneration, we subjected mice to ischemia-induced muscle damage by ligating the femoral artery. Muscle samples were harvested at 1, 2, 4, and 7 days post injury (dpi). CD45+CD11b+F4/80+CD64+ macrophages were isolated and processed for RNA sequencing, Western Blotting, and CUT&Tag-sequencing to investigate gene expression, histone lactylation levels, and histone lactylation genomic localisation and enrichment, respectively. Results: We show that, over time, macrophages in the injured muscle undergo extensive gene expression changes, which are similar in nature and in timing to those seen after other types of muscle-injuries. We find that the macrophage histone lactylome is modified between 2 and 4 dpi, which is a crucial window for macrophage polarisation. Absolute histone lactylation levels increase, and, although subtly, the genomic enrichment of H3K18la changes. Overall, we find that histone lactylation is important at both promoter and enhancer elements. Lastly, H3K18la genomic profile changes from 2 to 4 dpi were predictive for gene expression changes later in time, rather than being a reflection of prior gene expression changes. Conclusions: Our results suggest that histone lactylation dynamics are functionally important for the function of macrophages during muscle regeneration.

O presente artigo apresenta os resultados quantitativos de uma pesquisa bibliográfica sobre a tradução de literatura de língua alemã no Brasil de 1900 a 2020. Após uma breve contextualização das traduções do alemão no Brasil, descreve-se a configuração do projeto e apresentam-se os principais resultados referentes a vários parâmetros: evolução temporal, os objetos traduzidos (autores, obras, épocas) e os agentes da tradução (tradutores e editoras). No final sugerem-se pesquisas mais detidas sobre o material coletado e caminhos para o aperfeiçoamento dos dados.

The demand for meat alternatives in different forms is increasing due to consumers’ awareness of climate change and the health benefits of plant-based ingredients compared to animals. However, current alternatives on the market do not fulfil consumers’ acceptance for taste and texture. Hence, different physical and biological processes, such as thermal treatment and fermentation, need to be investigated. This study reveals that the thermal treatment of legume flours (soy, pea and lentil) prior to single-strain fermentation with Leuconostoc citreum TR116 has a major impact on acidification, colour, texture and sensory properties due to the pregelatinisation of starch and denaturation of proteins. The thermal treatment of soy flour resulted in liquification, and it could not be used as a fermentation substrate. However, non-heat-treated soy flour was fermented for comparison. The highest total titratable acidity (TTA) was determined in fermented pea flour (PF) and fermented lentil flour (LF) after 48 h with 24.35 ± 0.29 mL 0.1 M NaOH/10 g and 24.98 ± 0.33 mL 0.1 M NaOH/10 g, respectively. Heat treatment prior to fermentation led to a reduction in TTA by 20 mL 0.1 M NaOH/10 g for both PF and LF. The loss of colour pigments during thermal treatment led to a lighter colour of the spreadable alternatives. Moreover, a harder texture (+13.76 N in LF; +15.13 N in PF) and a lower adhesiveness (−0.88 N in LF; −0.43 N in PF) were detected in spreadable meat alternatives that were treated with heat prior to fermentation. Cohesiveness was decreased by thermal treatment, and fermentation did not impact it. Fermentation without pre-heat treatment increased adhesiveness by 4.37 N in LF and by 2.36 N in PF—an attribute typical for spreadable meat. Descriptive sensory analysis showed that thermal treatment significantly decreased bitterness but increased crumbliness and reduced juiciness. On the other hand, fermentation without pre-heat treatment mainly influenced flavour by increasing fruitiness and decreasing beaniness, earthiness and off-flavours. In summary, thermal treatment prior to fermentation is powerful in reducing legume-typical off-flavours but is not suitable for the development of spreadable meat alternatives due to texture changes. However, this process can be very beneficial when producing sausage-like alternatives.

The growing awareness of the value of temporary use projects in reactivating unused buildings has led to their increased implementation and acceptance by local authorities and building owners. Encouraging such reactivation can help to address the large number of unused spaces in cities. Additionally, the construction sector’s substantial contribution to environmental damage amplifies the imperative for material-wise approaches to building reactivation, particularly when undertaken on a temporary basis. This study therefore delves into the overlooked dimensions of materialization and design within the realm of temporary use, shifting the discourse from the conventional emphasis on awareness raising to a more holistic approach encompassing sustainability and circularity. Through an in-depth case study analysis of nine pioneering temporary projects in and around Brussels, supported by semi-structured interviews and site visits, this paper first delves into the ‘material approach’ and the ‘design’ of temporary use projects. Second, through a comparative analysis of the cases, a framework of guidelines is prototyped, structured around three perspectives—materialization, design, and stakeholders—and their actionable steps, guidelines, and attention points. The proposed framework, presented and evaluated for the first time in academic research, serves as a proof of concept for the analysis and guidance of temporary use through three integrated perspectives towards resource efficiency. This innovative approach offers a holistic perspective that goes beyond mere standardization and awareness raising, acknowledging the complex dynamics inherent in temporary use projects and providing a comprehensive framework for analysis and action. Ultimately, translating this prototype into a user-friendly pamphlet holds potential to advance the knowledge in this field and facilitate the more effective and sustainable utilization of resources in temporary contexts.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

No abstract available.

Background Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes.Methods Embase®, Medline®, and EBM Reviews were searched via the OVID® platform on February 15, 2022. Conference proceedings, clinical trial registries, and global regulatory and reimbursement body websites were also searched. Eligible publications included clinical trials enrolling patients receiving cancer treatment with either PD-1, PD-L1, or CTLA-4 reporting outcomes including incidence or prevalence of ADAs and the impact of immunogenicity on treatment safety and efficacy. Reference lists of eligible publications were also searched. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and evidence quality assessment was conducted using the appropriate Joanna Briggs Institute Critical Appraisal tool.Results After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics.Conclusions Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes.

Abstract Background This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. Methods Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). Results A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. Conclusion Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction. Trial Registration NCT00374985

Abstract Multiple activations of individual genes during embryonic liver and HCC development have repeatedly prompted speculations about conserved embryonic signatures driving cancer development. Recently, the emerging discussion on cancer stem cells and the appreciation that generally tumors may develop from progenitor cells of diverse stages of cellular differentiation has shed increasing light on the overlapping genetic signatures between embryonic liver development and HCC. However there is still a lack of systematic studies investigating this area. We therefore performed a comprehensive analysis of differentially regulated genetic signaling pathways in embryonic and liver cancer development and investigated their biological relevance. Genetic signaling pathways were investigated on several publically available genome wide microarray experiments on liver development and HCC. Differentially expressed genes were investigated for pathway enrichment or underrepresentation compared to KEGG annotated pathways by Fisher exact evaluation. The comparative analysis of enrichment and under representation of differentially regulated genes in liver development and HCC demonstrated a significant overlap between multiple pathways. Most strikingly we demonstrated a significant overlap not only in pathways expected to be relevant to both conditions such as cell cycle or apoptosis but also metabolic pathways associated with carbohydrate and lipid metabolism. Furthermore, we demonstrated the clinical significance of these findings as unsupervised clustering of HCC patients on the basis of these metabolic pathways displayed significant differences in survival. These results indicate that liver development and liver cancer share similar alterations in multiple genetic signaling pathways. Several pathways with markedly similar patterns of enrichment or underrepresentation of various regulated genes between liver development and HCC are of prognostic relevance in HCC. In particular, the metabolic pathways were identified as novel prognostically relevant players in HCC development.

Abstract Background 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods/Design This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 μg once weekly for 8 weeks, followed by s.c. L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20

Abstract Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). Methods OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs. Results Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression. In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC. Conclusion The downregulation of OCT1 is associated with tumor progression and a worse patient survival.