Background:
Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more ...common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions.
Methods:
Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019–2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of “significant benefit” for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review.
Results:
While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting.
Conclusion:
Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.
► We define the terms “Green and Sustainable Software” and “Green and Sustainable Software Engineering”. ► We outline a conceptual reference model, the GREENSOFT Model, in order to support ...sustainable software development and usage. ► We set a framework for a life cycle of software, procedure models, metrics for sustainable software, and recommendations.
The resource and power consumption of ICT is still increasing, but also the benefits of ICT, e.g. in finding more efficient solutions for environmental problems. To date, it is not clear, whether the resource and energy savings through ICT overbalance the resource and energy consumption by ICT, or not. Up to now, manifold efforts of Green IT address the environmental aspects of sustainability considering computer hardware. However, there is still a lack of models, descriptions or realizations in the area of computer software and software process models. In our contribution, we first propose definitions of the terms “Green and Sustainable Software” and “Green and Sustainable Software Engineering”, then we outline a conceptual reference model, the GREENSOFT Model. This model includes a cradle-to-grave product life cycle model for software products, sustainability metrics and criteria for software, software engineering extensions for sustainably sound software design and development, as well as appropriate guidance.
Films of the semiconducting polymer poly4,8-bis(2-ethylhexyl)oxybenzo1,2-b:4,5-b′dithiophene-2,6-diyl3-fluoro-2-(2-ethylhexyl)carbonylthieno3,4-bthiophenediyl with 40% fluorinated monomers, denoted ...PTB7-F40, are spin coated out of different solvents onto PEDOT:PSS films. The influence of the used solvents chlorobenzene, 1,2-dichlorobenzene, and 1,2,4-trichlorobenzene as well as the influence of the additive 1,8-diiodooctane (DIO) is probed with grazing incidence small- and wide-angle X-ray scattering (GISAXS and GIWAXS). As seen with GISAXS, without DIO, the films are homogeneous and show roughness correlation with the PEDOT:PSS film surface. With DIO, an inner film structure with a size of 50–75 nm is found and the roughness correlations weaken. In addition, as seen in GIWAXS, the crystalline part of the films is influenced by the used solvent if DIO is added.
Findings are mixed regarding the association of electroencephalographic (EEG) attentional bias measures and body weight, with few studies measuring food craving or intake and no study reporting ...oscillatory measures.
EEG data were collected while 28 satiated adolescents (14 overweight/obese) viewed pictures of neutral, low-calorie food, and high-calorie food stimuli and rated their desire to eat, before having access to high-calorie snacks.
Unlike normal-weight adolescents, overweight/obese participants showed similar P300 amplitudes for high- and low-calorie food, and strongest event-related alpha band desynchronization for low-calorie stimuli. P300 amplitudes and state craving for low-calorie food furthermore predicted snack intake in this group.
The current research focus in overweight/obesity might need to be extended to include low-calorie food. While all participants showed an attentional bias for high-calorie food, it was the processing of low-calorie food which distinguished the two weight groups on measures of neural activity and which was associated with snack food intake in the overweight/obese group.
Aims
In primary central nervous system tumours, epithelial‐to‐mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in ...gliomas are almost exclusively expressed by glioma vessel‐associated pericytes (GA‐Peris). In this study, we aimed to identify the mechanism of EMT in GA‐Peris and its impact on angiogenic processes.
Methods
In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)‐β and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics.
Results
The number of PDGFR‐β‐ and αSMA‐positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG‐expressing pericytes displayed considerable morphological changes in GBM‐associated vessels, and TGF‐β induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF‐β antagonising antibody abolished these effects.
Conclusions
We provide evidence that in GA‐Peris, elevated SLUG expression is mediated by TGF‐β, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood–brain barrier in GBM.
In GBM‐vessel‐associated pericytes elevated SLUG expression, paralleled by the induction of cell proliferation, mitochondrial activity and cell migration, is induced by TGF‐β, a cytokine highly expressed by glioma cells. This indicates that GBM cells actively modulate neovascularization not only by modulating endothelial cells, but also by influencing the function and characteristics of adjacent vessel‐associated pericytes. This process might be responsible for the formation of an unstructured tumor vasculature as well as for the breakdown of the BBB in the tumor area.
Startle stimuli evoke lower responses when presented during the early as compared to the late cardiac cycle phase, an effect that has been called ‘cardiac modulation of startle’ (CMS). The CMS effect ...may be associated with visceral-afferent neural traffic, as it is reduced in individuals with degeneration of afferent autonomic nerves. The aim of this study was to investigate whether the CMS effect is due a modulation of only early, automatic stages of stimulus processing by baro-afferent neural traffic, or if late stages are also affected. We, therefore, investigated early and late components of auditory-evoked potentials (AEPs) to acoustic startle stimuli (105, 100, 95 dB), which were presented during the early (R-wave +230 ms) or the late cardiac cycle phase (R +530 ms) in two studies. In Study 1, participants were requested to ignore (n = 25) or to respond to the stimuli with button-presses (n = 24). In Study 2 (n = 23), participants were asked to rate the intensity of the stimuli. We found lower EMG startle response magnitudes (both studies) and slower pre-motor reaction times in the early as compared to the late cardiac cycle phase (Study 1). We also observed lower N1 negativity (both studies), but higher P2 (Study 1) and P3 positivity (both studies) in response to stimuli presented in the early cardiac cycle phase. This AEP modulation pattern appears to be specific to the CMS effect, suggesting that early stages of startle stimulus processing are attenuated, whereas late stages are enhanced by baro-afferent neural traffic.
•It is unclear if the cardiac modulation of startle (CMS) is due to early or late stages of stimulus processing.•We investigated auditory-evoked potentials (AEPs) in response to acoustic startle probes.•N1 amplitudes were lower for startle stimuli presented in the early cardiac cycle phase.•P2 and P3 amplitudes were higher for stimuli presented in the early cardiac cycle phase.•Early stages of startle processing are attenuated, whereas late stages are enhanced by baro-afferent neural feedback.
Emotion regulation is assumed to play an important role in depressive and anxiety symptoms in youth. However, the role of core components of emotion regulation, such as emotional awareness, is not ...well understood so far. Thus this meta-analysis aimed to examine the relationship between depressive and anxiety symptoms with emotional awareness in youth. A systematic literature search (PsycINFO, Medline, Google Scholar) identified 21 studies, from which 34 effect sizes were extracted. Results from random effects models showed that difficulties in emotional awareness were significantly correlated with a medium effect size for each, depressive and anxiety symptoms separately, and for their combined effects (overall outcome). Additionally, further analyses revealed that age was a significant moderator of the relationship between emotional awareness with depressive and anxiety symptoms, with younger samples (mean age ≤ 12 years) showing a stronger association between difficulties in emotional awareness and depressive and anxiety symptoms as compared to older samples (mean age > 12 years). The results suggest that emotional awareness may be of relevance for depressive and anxiety symptoms in youth. Future work is required to examine longitudinal developments, moderators, and mediators in multi-method approaches. Moreover, children and adolescents may benefit from interventions that aim to enhance emotional awareness.
Cognitive models of eating disorders propose that attentional biases for disorder-relevant stimuli contribute to eating disorder pathology. Empirical evidence of a contribution of attentional biases ...for binge eating disorder (BED) is still scarce. The aim of the present study was to assess attention engagement towards, and disengagement from, food stimuli in overweight females with BED (n = 25) and a group of overweight and obese women without BED (OW; n = 30). Participants completed a rapid serial visual presentation (RSVP) paradigm with food and neutral words as target stimuli. This task can be used to decompose an attentional bias for food stimuli into its stimulus engagement and stimulus disengagement components. Findings indicate that facilitated stimulus engagement for food stimuli over neutral stimuli was more pronounced in the BED group compared to the OW group. Conversely, there were no substantial disengagement effects in either group. Thereby, results support the idea that early attentional processes are biased in BED.
•We tested attentional bias for food stimuli in binge eating patients.•We found a facilitated engagement effect for food stimuli in patients with binge eating compared to controls.•Neither group experienced substantial difficulty to disengage from food stimuli.•Results support the idea that attentional engagement to food stimuli contributes to binge eating pathology.
Loss of control eating (LOC) constitutes a common eating pathology in childhood and adolescence. Models developed for adult patients stress a biased processing of food-related stimuli as an important ...maintaining factor. To our knowledge, however, no EEG study to date investigated the processing of visual food stimuli in children or adolescents with LOC. Adolescents with at least one self-reported episode of LOC in the last four weeks and a matched control group completed a modified Go/NoGo task, with a numerical target or non-target stimulus being presented on one side of the screen and an irrelevant high-calorie food or neutral stimulus being presented on the opposite side. Mean P3 amplitudes were analyzed. In Go trials, the LOC group's mean P3 amplitudes were comparable irrespective of distractor category, while for NoGo trials, mean P3 amplitudes were significantly higher when the distractor was a high-calorie food stimulus. This pattern was reversed in the control group. Results are interpreted in light of Gray's reinforcement sensitivity theory. They might reflect altered processes of behavioral inhibition in adolescents with LOC upon confrontation with visual food stimuli.
The aim of the current study was to examine the usage of spontaneous emotion regulation in eating disorders (ED). After watching a sad film clip, women with anorexia nervosa (
n
= 42), bulimia ...nervosa (
n
= 40), and a non-ED control group (
n
= 41) indicated on visual analogue scales to what extent they had used emotional acceptance, reappraisal, rumination and suppression to cope with their emotions during the film clip. Results revealed no differences between the groups with regard to levels of reappraisal. However, both ED groups used rumination and suppression to a greater extent, and acceptance to a lesser extent, than the non-ED control group. ED severity was predicted by spontaneous rumination and suppression. Results suggest that—when not instructed—individuals with anorexia and bulimia nervosa have a greater tendency to engage in maladaptive emotion regulation. In particular, spontaneous rumination and suppression seem to be closely related to ED pathology.
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