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Uncontrolled hypertension is associated with an increased risk of adverse clinical vascular outcomes and death. Hypertension management guidelines from China and the USA recommend initiation of antihypertensive pharmacotherapy with a single drug for patients without severe hypertension at presentation. Current European hypertension guidelines take a different approach and recommend the use of combination therapy from the time of diagnosis of hypertension for most patients. This article reviews the burden of hypertension in these countries, and summarises the evidence base for the use of antihypertensive combination therapy contained within a single tablet (single-pill combinations, SPC). Typically, half or less of populations from China, Europe and the USA who were found to have hypertension were aware of their condition, less than half of those received treatment, and fewer still achieved adequate blood pressure (BP) control. The reasons for the unaddressed burden of hypertension are complex and multifactorial, with contributions from factors related to patients, healthcare providers and healthcare systems. The use of SPCs of antihypertensive therapies helps to optimise adherence with therapy and is likely to result in superior BP control. There is a strong evidence base to support current European guideline recommendations on the initiation of antihypertensive therapy with SPCs for the majority of people with hypertension.

Diversity is a key driver of innovation and a critical component of success on a global scale. Countries that deploy strategies to foster greater inclusion of all inventors in the innovation lifecycle will ultimately be best positioned to maximize their gross domestic product and ensure economic prosperity. The U.S. is losing ground because it is not fully engaging a significant portion of the inventive talent pool. According to a 2019 report from the U.S. Patent and Trademark Office, the share of women among all U.S. inventor-patentees is only 12.8%. In an effort to understand factors that encouraged and discouraged academic women's participation in technology commercialization, a group of technology transfer professionals conducted a survey of academic women involved in innovation, invention and/or entrepreneurship. The 168 respondents were from public and private research institutions of varying sizes from all regions of the U.S. This paper outlines the key findings from the qualitative and quantitative data around the themes that emerged. It also puts forth a set of recommendations based on the survey feedback, follow-up interviews, and the collective experience of technology transfer professionals who work daily with academic innovators. It is our hope that these recommendations will provide valuable insights into concrete actions that can be taken to ensure systemic changes that foster greater engagement of academic women and other under-represented populations in all stages of the innovation lifecycle.

Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100 mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850 mg, 50/1000 mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet.The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48 h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUCTreated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100 mg), 26/25 (FDC 50/850 mg), and 26/24 (FDC 50/1000 mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUCThe new generic tablet formulations of sitagliptin 100 mg and the FDCs sitagliptin/metformin 50/850 mg and 50/1000 mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D).EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

Due to the growing importance of videos for B2B sales outreach, this study proposes an extended model based on the Corporate-Video Model by Büsching and Meidel (2016) and a qualitative survey with high-ranking company representatives. The findings comprise seven complementary categories: structure, communication, product display, information content, unique selling proposition, value-based selling, and dramaturgy of product videos. The model extension aids practitioners in analyzing and conceptualizing compelling B2B product videos.

Objectives Point-of-care (POC) measurement of thyrotropin (TSH) may facilitate prompt diagnosis of thyroid dysfunction. We evaluated the analytical performance of a new POC TSH assay (Wondfo). Methods TSH measurements were made from 730 consecutive, unselected subjects in an outpatient setting, using Wondfo in whole blood, capillary blood and serum or automated reference equipment (serum only). Results TSH measurements were user-independent. Total intra-and inter-assay variation (CV%) was 12.1 and 16.2%, respectively. Total CV% was 10.6–22.6% and 14.5–21.6% in serum and whole blood, respectively. Linearity was very good. Recovery rate was 97–127%. Prolongation of incubation time increased TSH results of 12% (13%) and 33% (35%) after 2 and 5 additional minutes in serum (blood), respectively. When measured simultaneously in two Wondfo devices, the slope of the regression line was 1.03 (serum) and 1.02 (blood), with Spearman’s correlation of 0.99 for both. TSH measurements between Wondfo and reference correlated strongly (r=0.93–0.96), though TSH measurements were lower with Wondfo (slopes of plots of measurements made using the two devices were 0.94 [serum vs. serum]; 0.83 [whole blood vs. serum] and 0.64 [capillary blood vs. serum]). Depending on sample material, TSH in capillary blood was lower vs. whole blood (slope: 0.82) and for whole blood vs. serum (Wondfo and reference method; slope: 0.69 and 0.83). Total haemolysis, but not elevated bilirubin or lipemia, disrupted TSH measurement. Conclusions The Wondfo system was straightforward to use without need for specialist technicians and demonstrated analytic performance suitable for clinical use for the diagnosis of thyroid dysfunction.

Directing our focus of attention appropriately during task execution can benefit outcome performance, cognitive efficiency, and physiological efficiency. For instance, individuals may benefit from adopting an external focus of attention (i.e., by focusing attention on the effects of one's movements on the environment) over an internal focus of attention (e.g., focusing on one's body movements). However, accounts concerning the theoretical functioning of such effects have primarily relied on hierarchical information processing perspectives; far less consideration has been given to potentially alternative explanations based on ecological dynamics, instances where an internal focus may be desirable over an external focus, and the associated applied implications. Within the present review, we: (a) outline the most recent developments in attentional focus research; (b) evaluate similarities and differences between information processing and ecological dynamics explanations of the focus of attention effect; (c) provide practical recommendations; and (d) discuss future research avenues. In doing so, a case is made for an “Ecological Dynamics Account of Attentional Focus” to act as an alternative to information processing-based hypotheses.

New generations of robots are designed to support humans with a variety of partially or fully automated services. Such flexible and mobile service robots cooperate with humans or even act completely independent. To achieve this, it is necessary to significantly improve their capabilities in terms of environment perception, data processing and movement. At the same time, they must meet the highest standards of reliability and safety. Innovative electronics enable the necessary improvements and thus appropriate robot behavior. The aim of the Bionic RoboSkin project is to enhance the possibilities of a robot platform that is capable of autonomously navigating its respective environment by means of a flexible bionic sensor skin. The sensor platform is an autonomous underwater vehicle [AUV] that is based on the bionic principles of a Manta Ray [1, 2, 3]. The newly developed sensor skin consists of a textile composite as a carrier for sensor elements and provides moisture-resistant electrical connections for energy supply and communication. The integrated sensor modules enable both the detection of touch and approach and the exploration of the environment. The functionality of the sensor skin is targeting two service robotics applications: autonomous surveying of underwater structures (e.g. inspection of pipelines) and semi-autonomous geo-exploration in difficult-to-access areas (e.g. monitoring in tunnel construction). As a result, the paper presents the concept of a modular packaging platform for the use in a harsh marine environment. The technologies used for the miniaturization of the sensor module by PCB embedding and for outer housing development will be discussed in detail and a strong focus is put on packaging material properties in sub-marine conditions.

Hypertension is a major cause of morbidity and mortality worldwide. Although current drug therapies can be effective, management of hypertension is closely linked to patient adherence to therapy. A fixed-dose combination (FDC) of bisoprolol and amlodipine has shown to be effective and convenient, and to significantly improve patient adherence.This narrative review evaluates recent evidence from four studies which explore the efficacy, safety, and adherence of FDC bisoprolol and amlodipine in patients with hypertension: one observational study; two randomized clinical trials (RCTs); and one indirect comparison analysis.All four studies support the efficacy of FDC bisoprolol and amlodipine in the management of hypertension, highlighting clinically meaningful reductions in systolic and diastolic blood pressure (BP), and high adherence. In a large cohort study exploring FDC bisoprolol and amlodipine in daily practice, high adherence improved BP and heart rate control versus baseline. In a Phase 3 RCT, FDC bisoprolol and amlodipine demonstrated superiority over monotherapies in BP control and a positive tolerability profile, further supporting its use to manage hypertension in second line following monotherapy. In another Phase 3 RCT, the combination of bisoprolol and amlodipine led to significant BP reductions versus monotherapy with amlodipine with a comparable safety profile. Finally, in the indirect treatment comparison, a low dose combination of bisoprolol and amlodipine showed a similar decrease in systolic BP compared with a maximum dose of amlodipine.This review adds to growing evidence supporting the efficacy, safety, and tolerability of FDC bisoprolol and amlodipine in managing hypertension.

Lifelong treatment with levothyroxine (LT4) is the mainstay of management for individuals with hypothyroidism. Many hypothyroid patients start LT4 treatment at a low dose (e.g. 25-50 µg), especially the elderly, those with residual thyroid function, those with low body weight, and those with significant (especially cardiac) comorbidities. Almost half of patients on LT4 replacement therapy demonstrate either under- or over-treatment. Many LT4 preparations have relatively large intervals between tablet strengths at the lower end of their dose ranges (providing 25 µg, 50 µg, and 75 µg tablets), which may represent a barrier to achieving the optimum maintenance treatment for some patients. The availability of intermediate tablet strengths of LT4 in the 25-75 µg range may facilitate precise and effective dose titration of LT4 and may also enable convenient maintenance regimens based on a single LT4 tablet daily, to support adherence to therapy.

Vildagliptin and metformin are two well-established oral antidiabetics with a complementary mechanism of action. Two new generic products, vildagliptin and its fixed-drug combination (FDC) with metformin, were tested for bioequivalence versus the approved originator reference products (Galvus® and Eucreas®).Three randomized studies with two-treatment, two-period, two-sequence crossover design were conducted in healthy adults. One study evaluated vildagliptin 50 mg tablets as single dose under fasting conditions. Vildagliptin-metformin FDC tablet strengths of 50/850 mg and 50/1000 mg were evaluated in separate studies as single dose under fed conditions, given 30 min after a standardized high-fat, high-calorie breakfast following 10 h overnight fasting. Blood samples for analysis were collected until 24 h after dosing in each study period. Bioequivalence between test (T) and reference (R) products required 90% confidence interval (CIs) for the geometric least square (LS) mean T/R ratio to be within 80-125% for the pharmacokinetic parameters, maximum plasma concentration (CThe 90% CIs of geometric LS means of T/R ratio for CThe new generic drug products of vildagliptin and the FDCs of vildagliptin and metformin demonstrated bioequivalence to the approved originator products and are therefore expected to provide similar therapeutic effects.

Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy.The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures.We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period.Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59).Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

Objectives: Our study evaluates the impact of adjuvant treatment with external beam radiotherapy (EBRT) combined with vaginal high-dose-rate brachytherapy (HDR BT) on health-related quality of life (HRQL) in patients with early-stage endometrioid endometrial carcinoma. Material and methods: We assessed HRQL of patients based on the EORTC QLQ-C30 questionnaire, with endometrial cancer specific HRQL module — EORTC QLQ-EN24. From March 2019 to April 2020 we enrolled 20 patients with early-stage endometrioid endometrial carcinoma, qualified for adjuvant treatment after hysterectomy. We compared the scores measured with the questionnaires at the beginning and at the end of the treatment. Results: There was a statistically significant decrease in the mean of global health status/quality of life assessed according to the EORTC QLQ-C30 scale, from 62.25 ± 13.12 at the beginning of the adjuvant radiotherapy to 55.85 ± 14.68 at the end of the treatment (p = 0.047). The mean appetite loss score was higher at the onset of the treatment as compared to its value after EBRT, 19.9 ± 27.33 vs 11.6 ± 19.52 (p = 0.043). Similarly to the mean constipation score, which was 29.85 ± 30.40 vs 11.6 ± 19.52 (p = 0.013). The mean diarrhoea symptom scale increased from 16.55 ± 20.16 to 56.75 ± 36.10 (p = 0.001). In the EORTC QLQ-EN24 scales, gastrointestinal symptoms scores were higher at the end of the treatment, (with the mean of 26.45 ± 22.76) as compared to 14.30 ± 16.52 at the beginning of EBRT (p = 0.003). Conclusions: Patients who receive adjuvant radiotherapy have decreased quality of life during the treatment reporting more serious gastrointestinal symptoms. The potential risk of treatment-related toxicity should be taken into account during the treatment planning process in order to minimize the deterioration of HRQL.

The aim of the study was to assess immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with cervical squamous cell carcinoma (SCC) staged IIB and IIIB, a relationship with selected clinical and histological parameters and its prognostic significance. This prospective study included 52 patients. Microvessel density (MVD) by CD34, lymphatic vessel density (LVD) by podoplanin and the Ki-67 index in specimens from paraffin blocks with cervical SCC tissues were examined. The relationship between these data and selected clinical and histological parameters was analysed. Positive correlation of MVD and the Ki-67 index was observed. No correlation was observed for MVD, LVD and the Ki-67 index in the tumour with staging, grading, length of treatment and squamous cell carcinoma antigen (SCC-Ag) concentration before and after treatment. The expression of MVD, LVD and the Ki-67 index in cervical SCC did not contribute to the risk of relapse and cancer-related death. No relationship was found for MVD, LVD and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum SCC-Ag level. MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death.Impact Statement

Atomic force microscopy is used to study the viscoelastic properties of epithelial cells in three different states. Force relaxation data are acquired from cells in suspension, adhered but single cells, and polarized cells in a confluent monolayer using different indenter geometries comprising flat bars, pyramidal cones, and spheres. We found that the fluidity of cells increased substantially from the suspended to the adherent state. Along this line, the prestress of suspended cells generated by cortical contractility is also greater than that of cells adhering to a surface. Polarized cells that are part of a confluent monolayer form an apical cap that is soft and fluid enough to respond rapidly to mechanical challenges from wounding, changes in the extracellular matrix, osmotic stress, and external deformation. In contrast to adherent cells, cells in the suspended state show a pronounced dependence of fluidity on the external areal strain. With increasing areal strain, the suspended cells become softer and more fluid. We interpret the results in terms of cytoskeletal remodeling that softens cells in the adherent state to facilitate adhesion and spreading by relieving internal active stress. However, once the cells spread on the surface they maintain their mechanical phenotype displaying viscoelastic homeostasis.

To compare changes in systolic and diastolic blood pressures (SBP, DBP) from baseline to following 8 weeks of treatment with a low dose combination of amlodipine 5 mg plus bisoprolol 5 mg versus up titration to the maximum daily dose of amlodipine 10 mg, in hypertensive patients uncontrolled by amlodipine 5 mg.Individual patient data (IPD) from a randomized clinical trial (RCT) comparing the combination versus amlodipine 5 mg (EudraCT Number: 2019-000751-13) and aggregated data (AgD) from a published RCT comparing amlodipine 10 mg versus amlodipine 5 mg were utilized in an anchored simulated treatment comparison (STC). The RCT with IPD was used to create models assessing how patients might respond to the combination if they were more comparable to those patients in the RCT with AgD. A population-adjusted indirect comparison of the treatment strategies was then conducted, using amlodipine 5 mg as an anchor.In the efficacy analyses, a total of 261 patients were included in the amlodipine 10 mg arm of the RCT with AgD; and a total of 178 patients in the low-dose combination arm of the RCT with IPD. Respectively, in the Amlodipine 10 mg arm and in the low-dose combination arm, the mean age was 54.3 years-old (Standard deviation [SD] 10.6), and 57.1 years-old (13.7); 8.7% and 18.8% of patients were diabetics; and the mean baseline SBP/DBP was 149.3 (12.0)/96.5 (4.7) mmHg, and 148.8 (8.2)/90.2 (7.6) mmHg. The final model for SBP and DBP included the following variables: baseline SBP, baseline DBP, duration of hypertension, age, concomitant diabetes, sex, smoking history (final model for SBP only), and body mass index (final model for DBP only). Mean treatment differences (standard error [SE]) at 8 weeks between the combination and uptitration were -1.6 mmHg (1.9) for SBP; and -3.3 mmHg (1.3) for DBP.In this indirect comparison, a more important decrease was observed in DBP with the low-dose combination as compared to the alternative therapeutic approach of up-titration from amlodipine 5 mg to amlodipine 10 mg. No meaningful difference was seen for SBP.

Cellular sorting and pattern formation are crucial for many biological processes such as development, tissue regeneration, and cancer progression. Prominent physical driving forces for cellular sorting are differential adhesion and contractility. Here, we studied the segregation of epithelial cocultures containing highly contractile, ZO1/2-depleted MDCKII cells (dKD) and their wild-type (WT) counterparts using multiple quantitative, high-throughput methods to monitor their dynamical and mechanical properties. We observe a time-dependent segregation process governed mainly by differential contractility on short (5 h) timescales. The overly contractile dKD cells exert strong lateral forces on their WT neighbors, thereby apically depleting their surface area. Concomitantly, the tight junction–depleted, contractile cells exhibit weaker cell–cell adhesion and lower traction force. Drug-induced contractility reduction and partial calcium depletion delay the initial segregation but cease to change the final demixed state, rendering differential adhesion the dominant segregation force at longer timescales. This well-controlled model system shows how cell sorting is accomplished through a complex interplay between differential adhesion and contractility and can be explained largely by generic physical driving forces.

The SCIP Optimization Suite provides a collection of software packages for mathematical optimization centered around the constraint integer programming framework SCIP . The focus of this paper is on the role of the SCIP Optimization Suite in supporting research. SCIP ’s main design principles are discussed, followed by a presentation of the latest performance improvements and developments in version 8.0, which serve both as examples of SCIP ’s application as a research tool and as a platform for further developments. Further, the paper gives an overview of interfaces to other programming and modeling languages, new features that expand the possibilities for user interaction with the framework, and the latest developments in several extensions built upon SCIP .

Oxygen concentration plays a crucial role in (3D) cell culture. However, the oxygen content in vitro is usually not comparable to the in vivo situation, which is partly due to the fact that most experiments are performed under ambient atmosphere supplemented with 5% CO2, which can lead to hyperoxia. Cultivation under physiological conditions is necessary, but also fails to have suitable measurement methods, especially in 3D cell culture. Current oxygen measurement methods rely on global oxygen measurements (dish or well) and can only be performed in 2D cultures. In this paper, we describe a system that allows the determination of oxygen in 3D cell culture, especially in the microenvironment of single spheroids/organoids. For this purpose, microthermoforming was used to generate microcavity arrays from oxygen-sensitive polymer films. In these oxygen-sensitive microcavity arrays (sensor arrays), spheroids cannot only be generated but also cultivated further. In initial experiments we could show that the system is able to perform mitochondrial stress tests in spheroid cultures to characterize mitochondrial respiration in 3D. Thus, with the help of sensor arrays, it is possible to determine oxygen label-free and in real-time in the immediate microenvironment of spheroid cultures for the first time.

We introduce a new class of real-valued monotones in preordered spaces, injective monotones. We show that the class of preorders for which they exist lies in between the class of preorders with strict monotones and preorders with countable multi-utilities, improving upon the known classification of preordered spaces through real-valued monotones. We extend several well-known results for strict monotones (Richter-Peleg functions) to injective monotones, we provide a construction of injective monotones from countable multi-utilities, and relate injective monotones to classic results concerning Debreu denseness and order separability. Along the way, we connect our results to Shannon entropy and the uncertainty preorder, obtaining new insights into how they are related. In particular, we show how injective montones can be used to generalize some appealing properties of Jaynes' maximum entropy principle, which is considered a basis for statistical inference and serves as a justification for many regularization techniques that appear throughout machine learning and decision theory., publishedVersion

Introduction: A phase I, open-label clinical trial in healthy male subjects was conducted to assess the pharmacokinetic and safety profile of an oromucosal cannabinoid spray (AP701) containing a lipid-based nanoparticular drug formulation standardized to ∆-9-tetrahydrocannabinol (THC). Methods: Twelve healthy male subjects received a single dose of AP701 (12 sprays) containing 3.96 mg THC. Plasma samples were drawn 10 min–30 h post dose for analysis of THC and the active metabolite 11-hydroxy-∆-9-THC (11-OH-THC). Results: The single dose of the applied oromucosal cannabinoid spray AP701 (12 sprays, 3.96 mg THC) resulted in a mean maximum plasma concentration (Cmax) of 2.23 ng/mL (90% CI 1.22–3.24) and a mean overall exposure (area under the concentration-time curve from time 0 to last measurable concentration [AUC0–t]) of 7.74 h × ng/mL (90% CI 5.03–10.45) for THC. For the active metabolite 11-OH-THC, a Cmax of 2.09 mg/mL (90% CI 1.50–2.68) and AUC0–t of 10.4 h × ng/mL (90% CI 7.03–13.77) was found. The oromucosal cannabinoid spray AP701 caused only minor psychotropic effects despite the relatively high dosage applied by healthy subjects. No serious adverse effects occurred. Overall, the oromucosal cannabinoid spray AP701 was well tolerated. Conclusion: Compared to currently available drugs on the market, higher AUC values could be detected for the oromucosal cannabinoid spray AP701 despite administration of a lower dose. These comparatively higher blood levels caused only minor psychotropic adverse effects. The oromucosal cannabinoid spray AP701 was well tolerated at a single dose of 3.96 mg THC. The oromucosal administration may provide an easily applicable and titratable drug formulation with a high safety and tolerability profile.

This research presents an application to capture production disruptions, e.g. missing parts or machine breakdowns, in the manual assembly of complex products and systems (CoPS). We validate the usability of this application by measuring time performance, potential resulting data accuracy, and user experience. The presented results stem from a single case study. This research conducts 51 usability tests. We show that the presented application has the potential to achieve a level of data accuracy above 97 % and a level of user experience rated as “good” by the user experience questionnaire. The application is now in operational use at a manufacturer of CoPS.

Tumor hypoxia is defined as a low oxygen level in tissue and is associated with poor clinical outcome after chemo-/radiotherapy and surgery in many solid tumor types. Positron Emission Tomography (PET) imaging provides a non-invasive means of measuring local variations in the uptake of hypoxia-targeted agents (e.g. FAZA or FMISO). Accurate quantification of uptake is critically dependent on the PET scanner's linear count rate performance. In the context of cervix cancer, high PET agent accumulation in the bladder, low uptake in the tumor, and their relative proximity makes an accurate quantification of the tumor's hypoxic fraction challenging. The purpose of this study was to estimate the impact of PET scanner non-linearity on PET-based estimation of hypoxic fraction.The impact of PET scanner non-linearity effect was assessed with a NEMA body phantom, using the cylinder as the "bladder-mimicking" compartment and the water filled background as a surrogate region for the tumor. A simple model of the non-linearity effect was then applied to a set of patient-derived FAZA-PET scans (N = 38) to estimate the impact of the non-linearity on the calculated hypoxic fraction (HF) for each patient.The NEMA body phantom measurements revealed a substantial overestimate of activity outside the injected "bladder mimicking" cylinder compartment. This uptake resulted in an overestimate in activity between 1.9 and 0.3 kBq/cc corresponding to distances from 1.0 - 7.0 cm from the cylinder. In the patient-derived PET images, the bladder-to-tumor distance ranged between 1.0 and 3.0 cm. For the 38 patients analyzed, the HF was demonstrated to decrease by 1.1-75.0 % [median 27.2 %] depending on distance and relative uptake levels. Additionally, the magnitude of the effect of the non-linearity was found to depend on the pre-scanning hydration protocol employed (p = 0.0065).Hypoxia imaging of tumors of the cervix is challenging due to patient specific activity accumulation in the bladder and the non-linear response of PET scanner performance. This can result in a substantial overestimate of the calculated hypoxic fraction in cervical tumors. Additional effort needs to be invested to improve the linearity of PET scanners in anatomical regions proximal to the bladder.

Sets are a construction within André Bazin’s “recreation of the world in its own image.” During the 1920s, advances in film stock (which improved image clarity) and better lenses (which expanded depth of field) meant that the visual fidelity of sets had to increase. Most critical was more sophisticated camera motion. Cranes could now take the camera into sets, which required more complete environments. Sets have mutated and spread ever since. Architects began working in the movie industry and movie people began working as architects. With the introduction of the first Disney theme park, this practice became codified and thematic placemaking has since proliferated globally. Sets later provided the blueprint for digital games, and as embodied in the game engine have reached virtual holism. Today, Industrial Light & Magic’s StageCraft pairs LED display walls with game engine technology on a soundstage called the Volume. StageCraft replaces both CGI and the traditional set with mixed reality, photorealistic digital environments. Filmmakers can also make design changes in real time and move these virtual backgrounds around the players. This article posits a new history of the spatial philosophy of set design in which the experiential mode of themed spaces, video games, and virtual reality each become a unified recombination of Bazin’s rigid theatre/ cinema dichotomy.

Manufacturing companies operate software for the manual collection of process data on the shop floor. A volatile utilization of such software by operators leads to insufficient data quality. The affected companies have difficulties to understand and improve the performance of their assembly processes. We design software to capture data on production disruptions for a manual assembly of complex products. This research investigates the operator's intention to use this software in a single case study. Thus, we conduct software tests and interviews with 51 potential users deploying the technology acceptance model 2 questionnaire. We find that the determinants perceived usefulness and job relevance are predictors for the intention to use software for manual data collection in the investigated context.

Kettle holes are found in young moraine landscapes and serve as an important habitat for amphibians. The loss of amphibians has been dramatic in recent decades, mainly because of the increase in land use intensity and deterioration of habitats e.g., kettle holes in agricultural landscapes. We monitored amphibian species on three organically managed farms in north-eastern Germany to get an overview of their occurrence and proof of reproduction to develop effective protection strategies. From 2016 to 2020, we investigated 50 kettle holes in cultivated fields. In 2018, we implemented the nature conservation measure ‘cutting back dense wooded belts’ in six of these kettle holes. Here, we focused on seven species considering four highly endangered species. We found six to seven species in up to 17 kettle holes in the 44 kettle holes without the measure ‘cutting back dense wooded belts’. Bombina bombina occurred at the most kettle holes (57%). The number of kettle holes where amphibians reproduced differed strongly. On average, at least one species reproduced at 58% of the kettle holes. Many kettle holes become overgrown with negative effects for amphibians due to the reduction in solar irradiation and higher water consumption. The nature conservation measure increased the number of species on average from two to four and the number of species with reproduction from one to three. It is one of more than 100 measures in the ‘Farming for Biodiversity’ project that farmers can choose to receive a nature conservation certificate, which can be used for marketing purposes.

Hypothyroidism is a common condition with a prevalence that varies according to local dietary iodine availability, gender and age. The symptoms of hypothyroidism are generally nonspecific, with considerable overlap with other conditions and with the consequences for the health of advancing age. These symptoms are not useful for diagnosing hypothyroidism and a thyroid function test is required for a firm clinical diagnosis. Lack of knowledge and understanding of hypothyroidism, and a tendency for many people to attribute the symptoms of hypothyroidism to other causes have led to substantial unawareness and often late diagnosis of hypothyroidism. Large observational studies and meta-analyses have shown that about 4-7% of community-derived populations in the USA and Europe have undiagnosed hypothyroidism. About four cases in five of these are subclinical hypothyroidism, with the remainder being overt hypothyroidism. The prevalence of undiagnosed hypothyroidism is higher in older subjects, in women, and some ethnic groups, consistent with diagnosed disease. More research is needed to quantify the clinical burden of undiagnosed hypothyroidism around the world, with educational efforts aimed at the public and healthcare professionals aimed at identifying and managing these individuals.

The SCIP Optimization Suite provides a collection of software packages for mathematical optimization centered around the constraint integer programming framework SCIP. The focus of this paper is on the role of the SCIP Optimization Suite in supporting research. SCIP's main design principles are discussed, followed by a presentation of the latest performance improvements and developments in version 8.0, which serve both as examples of SCIP's application as a research tool and as a platform for further developments. Further, the paper gives an overview of interfaces to other programming and modeling languages, new features that expand the possibilities for user interaction with the framework, and the latest developments in several extensions built upon SCIP., Comment: arXiv admin note: substantial text overlap with arXiv:2112.08872

The Physikalisch-Technische Bundesanstalt (PTB) is the national metrology institute of the Federal Republic of Germany and has been using synchrotron radiation (SR) for more than 40 years. Starting at the former facility BESSY I, the storage ring BESSY II (see corresponding article in this volume) has been used for this purpose since 1998, especially in the X-ray range, as well as PTB's own metrology light source (MLS) for lower photon energies since 2008. Both facilities are located in Berlin-Adlershof and are operated by the Helmholtz-Zentrum Berlin within the framework of contractual agreements with PTB. The basic motivation of the work is radiometry. The two storage rings MLS and BESSY II are used as primary source standards and cryogenic radiometers as primary detector standards. The article gives a brief overview of the present status, scientific highlights, the technological development and upgrade plans for the decade 2023–2033 as well as a perspective of next scientific challenges.

Context River landscapes represent hotspots for biodiversity and ecosystem services used and embraced by human agents. Changes in river landscapes are subjectively perceived by people and can be assessed through the lenses of cultural ecosystem services (CES) and sense of place (SOP). Objectives This study aims to assess people–place relationships in a river landscape by integrating SOP theory and the CES concept and critically reflecting on their interplay. Research objectives relate to meanings and attachments attributed by citizens to places and the influence of the physical environment and socioeconomic settings. Methods We employed a spatially meaningful place indicator in a public participation GIS survey, combining meanings elucidated through a free listing exercise and multiple-choice questions. Statistical analyses were employed to investigate relationships between meanings, place attachment, and environmental and social variables. Results The results showed that (1) place meaning assessments can complement place attachment data by enhancing the understanding of relationships to biophysical and socioeconomic variables, and (2) combinations of both assessment approaches for place meanings showed that CESs were reflected in many free listed meaning types, dominantly related to forms or practices, but neglect relational values, such as “Heimat” (i.e., in German expression of the long-standing connection to an area) or memories. Conclusions This paper explicates synergies between SOP theory and CES concept. CES research offers insights from spatial assessments, while SOP research provides theoretical depth regarding relational values linked to CES. This paper critically reflects the ostensible consent of understanding SOP as a CES and proposes considering SOP as an overarching theory for CES assessment.

The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of combinations of LT4 and T3 to provide a superior outcome to LT4 monotherapy for people with hypothyroidism, especially those with residual symptoms despite thyrotropin-optimized LT4. This review seeks to provide an overview of currently available evidence on combination (LT4 + T3) therapy to be used for personalized medicine in patients with hypothyroidism. A number of randomized, controlled trials (RCTs) have failed to demonstrate superiority for the combination therapy approach, largely due to non-physiological T3 doses. However, patients with hypothyroidism are highly heterogeneous in terms of their residual thyroid function, individual set points for optimal thyroid homeostasis and for the presence or absence of polymorphisms in deiodinase enzymes in tissues that activate and deactivate circulating thyroid hormones. Accordingly, these RCTs may have failed to demonstrate benefits of combination therapy in individual hypothyroid phenotypes. The pharmacokinetics of LT4 and T3 also differ, which is a barrier to their co-administration. Future clinical trials using LT4 + T3 tablets better suited for combination therapy will resolve the outstanding research questions relating to the place of LT4 + T3 combination therapy in the management of hypothyroidism.

The impact of the e-economy has been observable in almost all the sectors of the national economies of the states in the last few years. The growing influence of this phenomenon is due to development of the Internet, which has already become a viable part of almost all the business activities including buying and selling. Therefore, it can be assumed that the area of e-commerce will have an increasing impact, not only on national economic development, but on the express mail market, as well. The content of the article is designed to provide a comprehensive view of the interdependence between the level of economic maturity (the GDP gross Domestic Product) per capita in the PPS (Purchase Power Standard) indicator), development of the e-commerce (indicator B2C (Business to Customer) e-commerce turnover) and the number of express deliveries. Identifying the influence between the aforementioned indicators, it will be possible to take certain measures to support the development of the e-commerce market.