Bielefeld University

Objective We analyzed the long‐term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open‐label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults. Methods Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment‐emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent‐to‐treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression‐Improvement [CGI‐I] scale ratings) in patients enrolled as adults. Results A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7–1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was −66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was −36.2% vs −71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI‐I at last visit as rated by caregivers and investigators, respectively. Significance Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

Biological systems are frequently viewed as performing computations that are implemented by chemical transformations underlying the turn-over of their molecular components. In chemical reaction networks, computation may refer to at least two fundamentally different aspects: concentrations of molecules, and molecular structures. The latter can be captured by modeling chemical reactions as a rewriting system acting on structural formulae, i.e. labeled graphs. We investigate the computational power of double-pushout (DPO) graph rewriting restricted to chemical graphs and show that chemical graph rewriting is sufficient to emulate Turing machines and two-tag systems on polymeric graphs that act as tapes. Moreover, we raise the question whether chemistry, modeled as DPO graph rewriting together with some additional form of chemical programs, may be computationally universal in the strong sense, i.e. capable of computing any computable function on chemical graphs.

The two‐fold deprotonation of the C2‐arylated 1,3‐imidazolium salts (IPr‐Ar)X (1‐Ar)X (IPr‐Ar = ArC{N(Dipp)CH}2; Ar = Ph, 4‐Me2NC6H4 (DMP) or 4‐PhC6H4 (Bp); Dipp = 2,6‐iPr2C6H3) with nBuLi affords the so‐called anionic dicarbenes Li(ADC) (2‐Ar) (ADC = ArC{N(Dipp)C}2). 2‐Ar can be used to prepare a variety of main group heterocycles, however their structures in the solid‐state remained hitherto unknown. Herein reported single‐crystal X‐ray diffraction studies reveal an acetylide type [ArC{N(Dipp)}(Dipp)NC≡CLi)]n (3‐Ar) dimeric (n = 2) or trimeric (n = 3) molecular structure for 2‐Ar. Treatment of 3‐Ph with Et3B cleanly yields the monoanionic carbene Li[(ADC)(BEt3)] (4‐Ph) featuring a weakly coordinating anion embedded in the same molecular entity. 3‐Ar readily undergo reactions with CO2 and N2O to form the ring‐closing products Li[(ADC)(CO2)2] (5‐Ar) and Li[(ADC)N2O] (6‐Ar), respectively.

NR1B1/RARα expression is dynamically regulated in cytotoxic lymphocytes (CTLs) in tumors, but the importance of its expression in anti‐tumor CTLs remains unknown. RARα gene expression is upregulated in CTLs in tumor microenvironments (TME), but its protein expression is downregulated by retinoic acid. The role of RARα expression in regulating anti‐tumor effector CTL (Teff) differentiation is reported. Mice that over‐express RARα in T cells are defective in early Teff differentiation and fail to populate tumors. In contrast, RARα‐deficient CTLs are hyper‐active in making tumor‐populating Teff cells, suggesting that RARα represses Teff differentiation. Moreover, RARα negatively controls the trafficking receptor switch from the lymphoid to an effector type. Generation of chimeric antigen receptor (CAR) T cells with reduced RARα expression produces highly effective CAR T cells with enhanced anti‐tumor cytotoxicity. Mechanistically, upregulated RARα expression decreases the nuclear histone acetylase (HAT) activity, required for TCF1 to BATF transcription factor and trafficking switches during Teff differentiation. Additionally, RARα and BATF closely associate with each other on Teff‐associated genes on the chromatin for possible cross‐regulation. In sum, T cell‐expressed RARα is identified as a novel negative regulator and potential target of intervention in promoting anti‐cancer T cell immunity.

Zusammenfassung Seit der russischen Invasion der Ukraine am 24. Februar 2022 rückt das Thema „Krieg und Frieden“ verstärkt in den Fokus öffentlicher Proteste. Die Protestlandschaft ist jedoch stark fragmentiert. Dieser Beitrag identifiziert vier zentrale Protestcluster: klassisch pazifistische Friedensmobilisierungen, Solidaritätskundgebungen, extrem rechte Friedensproteste und ideologisch gemischte Mobilisierungen. Die Akteursgruppen agieren weitgehend unabhängig voneinander und unterscheiden sich in ihrer Interpretation des Russland-Ukraine-Krieges sowie in ihren politischen Ideologien, Zielen und Forderungen. Der Beitrag analysiert diese fragmentierte Protestarena und diskutiert die Herausforderungen, die sich aus dieser Fragmentierung für die klassische Friedensbewegung ergeben.

Social power is linked to approach and withdrawal motivational systems, with frontal alpha asymmetry (FAA) in the electroencephalogram (EEG) potentially reflecting these tendencies. Higher left-frontal activity suggests approach, while lower levels indicate withdrawal. In this study, we used a novel within-subject design to explore how social power affects FAA. Twenty-five participants completed an episodic recall task inducing high or low social power, or a neutral condition, in random order. EEG alpha power (8–12 hz) was measured to calculate FAA indices for frontal and parietal-occipital regions and compared to resting-state asymmetry. Results showed a significant increase in left-hemispheric activity during high social power recall, affecting both frontal and non-frontal regions, compared to low power and control conditions. Low social power was associated with the least left hemispheric activity. These findings highlight strong effects of social power on brain systems related to approach and avoidance but challenge the notion that FAA is confined to frontal regions. The study enhances understanding of the neural mechanisms behind social power and underscores the value of within-subject designs and baseline measurements in studying neural activity related alpha asymmetry and social power.

Background Whether, and how, infant characteristics and parenting quality interact is one of developmental psychology's key questions. However, whether specific interaction patterns replicate across cohorts or developmental outcomes is largely unknown. This study investigates whether infant characteristics and parenting quality are independent predictors (additive effects) of child outcomes or interact such that certain infants particularly suffer from poor parenting (diathesis stress), particularly benefit from good parenting (vantage sensitivity) or both (differential susceptibility). Methods Individual participant data from over 30,000 children from four prospective cohorts were pooled. Using a competitive‐confirmatory approach of model evaluation, 16 possible permutations of infant characteristics (temperament and birthweight), parenting (maternal‐reported stimulating and sensitive parenting) and later developmental outcomes (fluid and crystalised intelligence, internalising and externalising behaviour) were tested. The robustness of results was evaluated by subsequently varying analytic methods, using alternative parenting measures including observer reports and excluding covariates. Results AIC values in 10/16 analyses indicated infant characteristics acted independently of maternal‐reported parenting for predicting developmental outcomes. Interaction patterns indicating diathesis stress (4/16), vantage sensitivity (2/16) or differential susceptibility (0/16) were rare or absent. However, diathesis‐stress patterns were frequently found regarding birthweight and internalising behaviours, which were largely robust to methodological changes. Conclusions Developmental outcomes are more consistently explained by additive effects rather than by interaction effects.

Background Transtricuspid cardiac implantable electronic devices (CIEDs) complicate the management of tricuspid regurgitation (TR). Transcatheter tricuspid valve annuloplasty (TTVA) offers a promising approach due to minimal interaction with leaflets and transvalvular CIEDs, though real-world evidence is limited. Methods This bi-center, retrospective study includes 204 consecutive patients who underwent TTVA with the Cardioband (Edwards Lifesciences) for severe symptomatic TR. Patients were divided into CIED carriers and non-CIED carriers. CIED carriers were further classified into those with lead-associated TR (LTR-A) and those with TR unrelated to CIED leads (LTR-B). Results Among the 204 patients, 41 (20%) were CIED carriers. Of these, 24% had mixed TR etiology (functional and LTR-A), while 76% had predominantly functional TR (LTR-B). Compared to non-CIED-carriers, CIED carriers were more symptomatic (NYHA-FC > II; 93% vs. 89%; p = 0.026) with comparable TR severity at baseline. Intraprocedural success according to the Tricuspid Valve Academic Research Consortium was 68% in CIED carriers and 70% in non-CIED carriers (p = 0.851). LTR-A was associated with poorer TR reduction immediately after TTVA (p = 0.022). Overall safety was comparable, with right ventricular lead dislodgement occurring in one patient. Beyond that, CIED function remained unimpaired. At 30 days, echocardiographic follow-up showed comparable TR reduction (TR ≤ II: 56% vs. 68%; p = 0.219) and NYHA-FU ≤ II (63% vs. 70%; p = 0.524) in CIED-and non-CIED carriers, respectively. Conclusions TTVA achieves significant TR reduction, providing a safe and effective therapeutic option for TR treatment in CIED carriers. What is known? TTVA using the Cardioband has been approved for severe, symptomatic TR patients, however data on the safety and efficacy in CIED carriers is lacking. What the study adds? Intraprocedural success and safety were comparable in CIED and non-CIED carriers treated with TTVA. Subgroup analyses showed a trend towards worse outcome and efficiency of TTVA in patients with LTR-A. Postinterventional CIED interrogations did not show critical technical issues. Graphical abstract Intraprocedural success and TR reduction following TTVA in CIED- and non-CIED-carriers. Blue arrows indicate CIED lead trajectory through tricuspid valve. Safety and efficacy of TTVA in CIED- and non-CIED carriers with symptomatic TR BL Baseline, FU = 30-day Follow Up, LTR-A Lead-associated Tricuspid Regurgitation, type A, LTR-B Lead-associated Tricuspid Regurgitation, type B, TR Tricuspid Regurgitation, TTVA Transcatheter Tricuspid Valve Annuloplasty

In land plants, one of the processes vital to cope with environmental changes is the accumulation of photoprotective flavonoids such as flavonols and anthocyanins. The inactivation of SUCROSE NON-FERMENTING1 RELATED PROTEIN KINASE1 (SnRK1), which acts in a chloroplast-derived sugar signalling pathway, permits the activation of flavonoid biosynthesis in high-light. The present study provides genetic evidence that SnRK1 acts upstream of PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP1), encoding a crucial transcription factor that activates the anthocyanin branch of flavonoid biosynthesis during high-light acclimation. A time-resolved expression analysis indicates a two-phasic suppression of MYB-LIKE2 (MYBL2), a repressor of anthocyanin production, involving SnRK1 inactivation for anthocyanin accumulation during prolonged high-light exposure. Furthermore, overexpression of PAP1 resulted in the marked suppression of MYB11, MYB12 and MYB111 and FLAVONOL SYNTHASE1, initiating the flavonol branch of the pathway. Analysis of a flavonoid-deficient chalcone synthase mutant overexpressing PAP1 suggests that regulation of flavonoid biosynthesis is PAP1-dependent but independent of flavonoid intermediates and end products. It is proposed that PAP1 suppresses the flavonol branch by an unknown mechanism, thereby promoting the consumption of carbon building blocks for anthocyanin production to permit the fine-tuning of the pathway.

The prognosis for patients with recurrent or metastatic endometrial cancer has historically been poor, with a 5-year survival rate of only 20–25%. Traditional treatment approaches, such as chemotherapy and hormonal treatments, have had limited clinical success. However, advances in the molecular classification of these tumors have revolutionized treatment approaches by enabling precise prognostic evaluations and the development of targeted therapies, which have significantly improved outcomes, particularly in advanced stages. To facilitate personalized treatment, molecular analyses should ideally be conducted at the time of initial diagnosis. Treatment decisions should always be made within an interdisciplinary framework, taking into account the patient’s preferences, general condition, disease extent, and prior treatments. In conclusion, advances in tumor biology and the development of innovative treatments have markedly improved the prognosis of patients with advanced endometrial cancer. Nonetheless, further research, particularly prospective studies focusing on long-term outcomes and side effect management, are essential to optimize care and refine treatment strategies.

Moderation effects in longitudinal structural equation models are often analysed using latent variable product terms, which can be complex and difficult to estimate, especially in large models with many panel waves. An alternative approach for categorical moderation variables is the simpler technique of multiple-group comparisons. This method allows for straightforward model specification and precise differentiation of effects in complex models. This tutorial demonstrates multiple-group comparisons using examples based on developmental trajectories of juvenile delinquency. These trajectories are modelled via a latent growth curve approach, treating the variables as count data and applying Bayesian estimation using the software Mplus. The results are processed using the R programming language. This method addresses challenges associated with maximum likelihood estimation, particularly for latent growth models with count variables and additional exogenous latent variables. The analysis examines group differences by gender and school type in the trajectories of an unconditional growth model. It also examines the effect of legal norm acceptance on these trajectories using a conditional growth model. The moderating effects of gender and school type on these effects are analysed separately. The results reveal group differences of gender and school type for the unconditional growth model, while the conditional growth model highlights a moderating effect of school type on the relationship between legal norm acceptance and growth trajectories.

Introduction The EQ Health and Wellbeing Short (EQ-HWB-S) is a new 9-item instrument designed to generate utility values. However, its length makes traditional preference elicitation challenging. The Online elicitation of Personal Utility Functions (OPUF) approach has been tested as a potential solution. This study aimed to assess the test-retest reliability of OPUF for valuing the EQ-HWB-S. Methods The OPUF survey was administered twice, two weeks apart, to 220 German participants, including 73 from the general population and 147 patients with diabetes or rheumatic disease. Test-retest reliability was evaluated at individual and aggregate levels, examining dimension rankings, swing weights, level weights, and anchoring factors. Continuous data were analysed using the intraclass correlation coefficient (ICC), and ranking data were compared using Spearman’s correlation coefficient. Individual and aggregate level utility decrements were assessed using ICC and t-tests. Results Approximately 36% of participants had significantly correlated dimension ranks, with 42% selecting the same top-ranked dimension. Poor agreement was shown in 70% of ICC values for individual dimension swing weights. For intermediate level weights, ICC values showed poor agreement in 70% and moderate agreement in 30% of responses. The kappa for individual pairwise comparison tasks was 0.64 (95% CI: 0.54–0.75) showing moderate agreement; however, the ICC for individual-level anchoring factors was 0.12 (p < 0.05), indicating poor agreement. Aggregate utility decrements across dimensions were similar. Conclusion The OPUF approach generates reliable aggregate value sets for the EQ-HWB-S, but further exploration is needed to understand and address the reasons behind inconsistencies at the individual level.

The social and legal treatment of prostitution varies between countries. We examined attitudes toward prostitution (ATP) and their susceptibility to persuasion in three countries: Norway, where prostitution is illegal; Spain, where prostitution is not explicitly regulated in the law; and Germany, where prostitution is legal. Participants (total N = 579) read arguments in favor of either legalization or abolition of prostitution or no arguments. Then they reported their ATP, judged the consequences of abolishing prostitution, and completed measures of feminism, political orientation, and sociosexuality. Results showed that, as hypothesized, ATP scores (1) reflected the countries' legislation, being most positive in Germany and least positive in Norway, (2) were affected by arguments only in Spain, where the legal situation is ambiguous, and (3) were meaningfully correlated with other attitudes across countries. These findings highlight the association of legal frameworks with attitudes, suggesting that national legislation can shape social norms and perceptions of prostitution. Additionally, the varying susceptibility to persuasive messages across different legal contexts underscores the role of legal ambiguity in shaping openness to attitudinal change. Keywords: attitudes, culture, Germany, legal norms, Norway, prostitution, sex work, Spain.

Background Chronic diseases, such as type 2 diabetes, are responsible for a substantial proportion of global deaths and are marked by an increasing number of people that suffer from them. Our objective is to systematically investigate the analytical determination of the drift in prevalence peaks over calendar-time and age, with an emphasis on understanding the intrinsic attributes of temporal displacement. This aims to enhance the understanding of disease dynamics that may contribute to refining medical strategies and to plan future healthcare activities. Methods We present two distinct yet complementary approaches for identifying and estimating drifts in prevalence peaks. First, assuming incidence and mortality rates are known, we employ a partial differential equation that relates prevalence, incidence, and mortality. From this, we derive an ordinary differential equation to mathematically describe the prevalence peak drift. Second, assuming prevalence data (rather than incidence and mortality data) are available, we establish a logistic function approach to estimate the prevalence peak drift. We applied this method to data on the prevalence of type 2 diabetes in Germany. Results The first approach provides an exact mathematical prescription of the trajectory of the prevalence peak drift over time and age, assuming incidence and mortality rates are known. In contrast, the second approach, a practical application based on available prevalence data, demonstrates the prevalence peak dynamics in a real-world scenario. The theoretical model, together with the practical application, effectively substantiates the understanding of prevalence peak dynamics in two different scenarios. Conclusion Our study shows the theoretical derivation and determination of prevalence peak drifts. Our findings underpin the dynamic nature of chronic disease prevalence, highlighting the importance of considering the related age-dependent trends for planning future healthcare activities.

Background The increasing complexity of patients’ health needs has led to the expansion of nursing practices in primary health care (PHC) globally. The corresponding rearrangements of the care process have promoted more horizontal relationships and interprofessional collaboration between nurses and physicians. Our study analyzes the current forms and prospects of nurse‒physician collaboration in the context of expanding nursing practice in PHC in Brazil and Germany. Methods We hosted 9 focus groups (4 in Brazil and 5 in Germany) featuring a total of 23 stakeholders who were involved in PHC policy making and 25 practicing nurses and physicians. Brazil and Germany were subjected to comparative analysis using the thematic coding approach suggested by Flick. Results Regarding the current forms of nurse‒physician collaboration, focus group participants identified the opportunities and obstacles exhibited by the PHC models employed in their respective countries. In both countries, nurses’ contributions to PHC were associated mainly with the task of meeting complex health needs; however, promoting nurse engagement is challenged by the predominance of physicians’ power in health care policies and practices. With respect to future trends in the expansion of nursing practices in collaboration with physicians, all participants in Brazil supported a complementary approach that focused on increasing the autonomy of nurses in PHC; in Germany, mixed opinions were expressed regarding this issue, with medical stakeholders and some general practitioners (GPs) insisting on a delegation-based approach. Conclusions Our study contributes to the literature by highlighting the opportunities and obstacles associated with interprofessional collaboration in the context of expanding nursing practice in PHC. The study highlights the willingness of both nurses and physicians to increase their level of collaboration by encouraging broader nursing practices. However, the power imbalance and hierarchical relations hinder the progress of collaboration between PHC nurses and physicians based on the logic of interprofessionality. The contrasting perspectives, which emphasize an autonomous interprofessional relationship and collaboration based on a subordinate relationship in the context of persistent medical hegemony, reflect certain contextual aspects of these health systems and conceptual approaches to care practices.

Path integration is a key navigation mechanism used by many animals, involving the integration of direction and distance of path segments to form a goal vector that allows an animal to return directly to its starting point. While well established for animals walking on solid ground, evidence for path integration in animals moving without ground contact, such as flying insects, is less clear. The review focuses on flying Hymenoptera, particularly bees, which are extensively studied. Although bees can use flight distance and direction information, evidence for genuine path integration is limited. Accurately assessing distance travelled is a major challenge for flying animals, because it relies on optic flow—the movement of visual patterns across the eye caused by locomotion. Optic flow depends on both the animal’s speed and the spatial layout of the environment, making it ambiguous for precise distance measurement. While path integration is crucial for animals like desert ants navigating sparse environments with few navigational cues, we argue that flying Hymenopterans in visually complex environments, rich in objects and textures, rely on additional navigational cues rather than precise path integration. As they become more familiar with an environment, they may iteratively refine unreliable distance estimates derived from optic flow. By combining this refined information with directional cues, they could determine a goal vector and improve their ability to navigate efficiently between key locations. In the case of honeybees, this ability also enables them to communicate these refined goal vectors to other bees through the waggle dance.

Background Smartphone-based alerting of community first responders to out-of-hospital cardiac arrest (OHCA) is associated with enhanced survival. Community first responders are volunteers, who are dispatched by the emergency dispatch centre, if they are in close proximity to an OHCA to decrease time until first chest compression. For a community first responder system to be successful, it is essential to recruit and retain as many qualified community first responders as possible. This study evaluates the appraisal and retention rate of an app-based community first responders system over a period of 3 years. Methods A longitudinal study among community first responder in a rural northern Germany was conducted using an online-survey. A questionnaire (7 open questions, 22 single choice questions and 2 multiple choice questions) was distributed to all community first responders (FR) via e-mail in October 2018, 2019 and November 2020. Ethical approval was obtained, informed consent was given by all participants. Results The response rate was 69%, 43% and 38% in the first, second and third year, respectively. Three years after implementing the system 96% of the users stated they still had the app installed. After the first year, 21% of participants observed improvements. In the second year, this number was 15%, and 31% in the third year. The opinion regarding the medical benefit of the app was stable. Nine out of ten participants would recommend the app to others. Of all participants 70% identified as male and 66% were 35 years old or younger. Main barrier to using the app was excessive „battery consumption“. Conclusions The community first responder system attracts a predominantly young and male user base. The retention rate of 96% over the three years observation period is high. The main barrier to app usage is excessive battery consumption. The users’ positive perceptions regarding the app’s medical advantages and the favorable perception of its functionality have resulted in a steadfast high recommendation rate.