Genetic factors are recognized as risk factors for statin-associated muscle symptoms (SAMS), which are the most common cause of statin intolerance. The aim of this study was to determine whether there is an association between polymorphisms 1236C > T, 2677G > T/A, and 3435C > T in the ABCB1 gene, encoding the efflux transporter of statins, and SAMS, as results on this topic are still controversial. A cross-sectional study was conducted on patients with or without SAMS using atorvastatin. The influence of non-genetic variables on SAMS was also evaluated. Our results show that patients with TT genotype in 1236C > T, 2677G > T/A, and 3435C > T polymorphisms had higher risk of developing SAMS, compared to wild type and heterozygous carriers together (OR 4.292 p  = 0.0093, OR 5.897 p  = 0.0023 and OR 3.547 p  = 0.0122, respectively). Furthermore, TTT/TTT diplotype was also associated with a higher risk of SAMS, OR 9.234 ( p  = 0.0028). Only family history of cardiovascular disease was found to be a risk factor for SAMS, in addition to the known non-genetic variables. We believe that ABCB1 genotyping has great potential to be incorporated into clinical practice to identify high-risk patients in a timely manner.

We introduce the theory of high-order harmonic generation by aligned homonuclear diatomic cations using a strong-field approximation. The target cation is represented as a system which consists of two atomic (ionic) centres and one active electron, while the driving field is either a monochromatic or bichromatic field. For a linearly polarised driving field, we investigate the differences between the harmonic spectra obtained with a neutral molecule and the corresponding molecular cation. Due to the larger ionisation potential, the molecular cations can withstand much higher laser-field intensity than the corresponding neutral molecule before the saturation effects become significant. This allows one to produce high-order harmonics with energy in the water-window interval or beyond. Also, the harmonic spectrum provides information about the structure of the highest-occupied molecular orbital. In order to obtain elliptically polarised harmonics, we suggest that an orthogonally polarised two-colour field is employed as a driving field. In this case, we analyse the harmonic ellipticity as a function of the relative orientation of the cation in the laser field. We show that the regions with large harmonic ellipticity in the harmonic energy-orientation angle plane are the broadest for cations whose molecular orbital does not have a nodal plane. Finally, we show that the molecular cations exposed to an orthogonally polarised two-colour field represent an excellent setup for the production of elliptically polarised attosecond pulses with a duration shorter than 100 as.

Human serum albumin (HSA) is one of the most important transporters for drugs in the systemic circulation. In this study, we investigated the interaction of rosuvastatin (ROS) and atorvastatin (ATO) with HSA. Binding of a drug molecule to HSA significantly affects the pharmacokinetics of the drug as it increases drug solubility in plasma, decreases toxicity and protects molecules from oxidation. This study was made using fluorescence spectroscopy and molecular modeling approach. Fluorescence spectra were recorded for two different statins brands at seven different concentrations. The results revealed that both statins (ROS and ATO) cause the fluorescence quenching of the HSA solution. ROS and ATO binds strongly to HSA with the binding constant (Kb) of 1.0246×106 and 0,9018×106, respectively. In addition, it was observed that high concentrations of ATO cause a shift of the emission maximum towards longer wavelengths (red-shift), which may be due to the unfolding of protein chains or denaturation. Furthermore, it was calculated that HSA possesses one binding site for ROS and ATO. Results from molecular docking showed that ROS has a higher affinity for Sudlow site I compared to Sudlow site II and the main binding forces are hydrogen bonds. ATO has nearly equal affinity for both binding sites on HSA, and the main binding forces are hydrophobic interactions.

The purpose of the present study is to propose an interval-valued type 2 fuzzy set (IT2FS)-based analytic hierarchy process (AHP) framework to unfold the critical challenging factors influencing the sustenance and growth of the Indian tea industry. The current work follows an expert opinion-based group decision-making approach. The challenging factors have been identified through a literature review and finalized after a pilot study based on the opinions of professionals, consumers, and experts. Finally, the critical challenging factors and sub-factors have been figured out through analysis of the responses of the experts. To offset the subjective bias, an IT2FS-based granular analysis has been carried out. The findings reveal that market diversification and productivity are the central issues. Additionally, it is important to give attention to improving the quality of the products, increasing the use of modern technology and organic farming, and developing a variety of products. The result shows a considerable level of consistency in the group decision-making (CR < 0.1) for all pairwise comparisons. The present work shall be of use to formulate appropriate strategies and policy decisions. It shows a robust application of IT2FS-AHP for complex decision-making in real life.

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration‐resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher‐grade tumors, although no significant association between HOXB13 expression and recurrence or disease‐specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor‐negative castration‐resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non‐prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration‐resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.

Subdivision of 2D polygons is the basis of many computational geometry algorithms and procedural modeling methods. Existing tools for space subdivision often require the assistance of users and cannot perform subdivision on all types of shapes (rectangular, axis-aligned, convex, and irregular). In this work, an open-source graphical desktop tool for drawing and automatic subdivision of arbitrary 2D polygons is introduced. An algorithm for subdivision of all shape types was developed. The algorithm is based on the usage of polygon bounding boxes, intersection edges and detection of polygons from newly formed edges. A dataset of 60 examples of all shape types was collected and successfully drawn by using the tool. Iterative subdivision was performed on all examples. Shape simplification was fully successful only for axis-aligned shapes. Partial simplification with leftover elements taking up less than 5% of overall polygon area was successful after 5 iterations for axis-aligned, and 10 iterations for convex and irregular shapes on average. This indicates that the tool and subdivision algorithm can be used for simplification of complex shape types with arbitrarily small leftover element area.

Sufficient conditions are given for planar cooperative maps to have the qualitative global dynamics determined solely on local stability information obtained from fixed and minimal period-two points. The results are given for a class of strongly cooperative planar maps of class $ C^1 $ C1 on an order interval. The maps are assumed to have a finite number of strongly ordered fixed points, and also the strongly ordered minimal period-two points. Some applications are included.

Die Paderborner Gastdozentur für Schriftstellerinnen und Schriftsteller ist eine der ältesten Poetikdozenturen in den deutschsprachigen Ländern. Zwanzig Jahre nach ihrer Gründung kamen 2002/03 im Laufe von zwei Semestern alle bis dahin nach Paderborn berufenen Poetikdozentinnen und -dozenten noch einmal zu Lesungen an die dortige Universität und traten so für das Publikum nacheinander in den Dialog. 2023, nach insgesamt 40 Jahren „Paderborner Gastdozentur für Schriftstellerinnen und Schriftsteller“, präsentieren die Veranstalter eine andere Art der Begegnung: zum einen mit den Beiträgen eines Symposiums zu den Werken Ingo Schulzes und Frank Witzels, die die 40. Paderborner Gastdozentur gemeinsam wahrgenommen und ihre Poetikvorlesungen buchstäblich im Dialog gehalten haben. Zum anderen versammelt das Sonderheft eine Reihe von Beiträgen, die jeweils zwei der in den zurückliegenden Jahren geladenen Poetikdozentinnen und -dozenten gemeinsam betrachten und deren Werke in einen spannungsvollen virtuellen Dialog eintreten lassen.

Despite the positive effects of green infrastructure on people and the environment, it is still rarely integrated in public facilities such as schools. The main reason for this is a lack of knowledge about financing options. To fill this gap, the research project MehrGrüneSchulen (Engl.: More Green Schools) develops financing scenarios for green infrastructure in Austrian schools. This case study describes these developed scenarios, which use the principles of crowdsourcing and crowdfunding as well as the newly named principle of chain building. The idea of chain building is to motivate schools that have already successfully financed and built a low-cost greening system to present this process to another school in such a way that they are able to do the same themselves and eventually explain the process to a further school to continue this chain reaction. For the proposed funding scenarios to be effective, there is a need for innovation in education, with a focus on inter-school participation and networking. For this reason, the possible synergies of an online networking platform are discussed, which would help to connect schools and thus further improve the impact of the proposed fundraising processes.

Abstract Alpha-mannosidosis is an inherited rare disorder of mannose-containing oligosaccharides metabolism that is currently treated by enzyme replacement therapy (ERT), bone marrow transplantation (BMT), or supportive therapy (ST). However, the relative cost-effectiveness of these treatment options is yet unknown. Our study aimed to compare the cost-effectiveness of the treatment options for mild to moderate alpha-mannosidosis. The study is based on a modeling approach using a Discrete-Event Simulation model to generate and simulate the course of the disease under the influence of each of the treatment options: ERT, BMT, and ST. The model had a lifetime horizon and was made from the perspective of the Serbian Health Insurance Fund. Currently, available causal therapy of mild to moderate alpha-mannosidosis with velmanase alpha enzyme replacement is not cost-effective compared with supportive therapy (ICER = 941,587,152 RSD) or bone marrow transplantation (ICER = −398,412,755 RSD). Bone marrow transplantation can be cost-effective compared to supportive therapy (ICER = 6,032,689 RSD), but only if the willingness-to-pay threshold is increased to 9 gross domestic products (GDP) per capita per QALY gained. According to the current threshold, velmanase-alfa is not cost-effective compared to BMT or ST. To make alfa-mannosidosis therapy widely accessible to patients, criteria for assessing the cost-effectiveness of orphan drugs must include not only the absolute value of ICER but other aspects like equity weightings of QALYs, risk-sharing, reimbursement of severe forms of a disease only, or availability of dedicated funding.

What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries.

Purpose This study aims to propose a novel mirroring digital content marketing (MDCM) framework that extends the current consumer-based digital content marketing (DCM) framework to encompass the provider’s perspective. Relying on the stimulus–organism–response theory, the authors posit that content stimuli influence behavioural engagement responses that, respectively, mirror the motives and self-reported engagement from the consumer-based DCM. Design/methodology/approach To empirically verify the provider side of the MDCM framework, the authors used one newsletter and one matching website with corresponding 117 weekly data points. Data were drawn from three sources for six countries: newsletter content stimuli, newsletter performance indicators and Google Analytics metrics on matching website performance. OLS and panel regressions were used to analyse the data and generate results. Findings The results show that content stimuli do explain the behavioural engagement responses of consumers recorded by the provider. However, the effects of the different stimuli are inconsistent: functional stimuli have both positive and negative effects, while social stimuli positively impact the behavioural engagement response. The authors further show that the newsletter engagement response influences subsequent engagement responses across channels (e.g. via the linked news media website). Research limitations/implications Further research definitely needs to empirically verify the connection between two sides of the MDCM framework. As proposed by authors, provider-based stimuli are corresponding to the consumer-based motivations, however, which stimuli are triggering which motivations and how they can consequently be translated to both consumer- and provider-based behavioural engagement is still an open question. Different theoretical lenses could be taken in the usage of MDCM framework. Practical implications Our observations are relevant for marketers that want to use certain stimuli in their digital content, in particular a content introduced in the newsletter and the website. The authors show that stimuli are indeed related to the behavioural engagement response of consumers and that various stimuli impact engagement differently. Furthermore, the recommendations for the marketing managers of news media are to use priming across the platforms in their Web communication strategies. Originality/value This study proposes and empirically tests the provider side of the MDCM framework across two news media channels, focusing on behavioural engagement responses.

The nucleation kinetics of ice were investigated with four different types of aqueous solutions. The studied aqueous solutions, i.e., sucrose solution, ionic liquid (IL) solution, pyrolysis oil extract (PO) solution, and acetone‐1‐butanol‐ethanol (ABE) solution, were concentrated by batch suspension freeze crystallization. The nucleation kinetics were investigated using a temperature response method which results in data on nucleation rate per crystal. The obtained nucleation rate per crystal value can be used when dimensioning continuous crystallization processes: the nucleation rate per crystal is inversely proportional to the residence time in continuous crystallization. The subcooling degrees for different solutions were in the range of 0.33 °C to 1.89 °C. Aqueous sucrose solutions had the fastest nucleation kinetics. Ice crystallization from non‐ideal aqueous [DBNH][OAc] ionic liquid solutions required higher subcooling degrees and the nucleation rates per crystal were higher as well. Nucleation of ice formed from aqueous pyrolysis oil extract and aqueous ABE solutions occurred at a lower subcooling degree and the obtained nucleation rate per crystal values were lower.

As virtual worlds continue to rise in popularity, so do the expectations of users for the content of virtual scenes. Virtual worlds must be large in scope and offer enough freedom of movement to keep the audience occupied at all times. For content creators, it is difficult to keep up by manually producing the surrounding content. Therefore, the application of procedural modelling techniques is required. Virtual worlds often mimic the real world, which is composed of organized and connected outdoor and indoor layouts. It is expected that all content is present on the virtual scene and that a user can navigate streets, enter buildings, and interact with furniture within a single virtual world. While there are many procedural methods for generating different layout types, they mostly focus only on one layout type, whereas complete scene generation is greatly underrepresented. This paper aims to identify the coverage of layout types by different methods because similar issues exist for the generation of content of different layout types. When creating a new method for layout generation, it is important to know if the results of existing methods can be appended to other methods. This paper presents a survey of existing procedural modelling methods, which were organized into five categories based on the core approach: pure subdivision, grammar‐based, data‐driven, optimization, and simulation. Information about the covered layout types, the possibility of user interaction during the generation process, and the input and output shape types of the generated content is provided for each surveyed method. The input and output shape types of the generated content can be useful to identify which methods can continue the generation by using the output of other methods as their input. It was concluded that all surveyed methods work for only a few different layout types simultaneously. Moreover, only 35% of the surveyed methods offer interaction with the user after completing the initial process of space generation. Most existing approaches do not perform transformations of shape types. A significant number of methods use the irregular shape type as input and generate the same shape type as the output, which is sufficient for coverage of all layout types when generating a complete virtual world.