Background: Bipolar disorder and attention-deficit/hyperactivity disorder are common comorbidities. Attention-deficit/hyperactivity disorder is commonly treated with stimulants (eg, methylphenidate), which, however, have been suggested to cause treatment-emergent mania in patients with bipolar disorder. Here, we assessed the risk of mania, depressive episodes, and psychiatric admissions after initiation of methylphenidate treatment in patients with bipolar disorder. Methods: Using Danish health registries, we identified all individuals registered with a diagnosis of bipolar disorder from January 1, 2000, to January 1, 2018, who were treated with methylphenidate. We applied a 1-year mirror-image model to compare the occurrence of mania, depression, and psychiatric admissions in the period leading up to and after methylphenidate treatment initiation. We furthermore assessed the trend in these outcomes from 4 years before to 1 year after initiation of methylphenidate treatment. Results: A total of 1043 patients with bipolar disorder initiated treatment with methylphenidate. The number of manic episodes decreased by 48% after methylphenidate treatment initiation (P = 0.01), both among patients using mood stabilizers (-50%) and among patients not using mood stabilizers (-45%). The number of manic episodes, however, peaked approximately 6 months before methylphenidate. The results were similar for the secondary outcomes. Conclusions: Initiation of methylphenidate treatment was not associated with an increased risk of mania in patients with bipolar disorder. A decrease in mania, depressive episodes, and psychiatric admissions was observed after methylphenidate. However, these decreases seemed to be driven by regression to the mean after clinical deterioration preceding methylphenidate treatment, rather than by the methylphenidate treatment itself.
The present study assessed for the first time the magnitude and dietary ecological source of total mercury (THg) exposure in a southern population of white-tailed eagles (Haliaeetus albicilla), an apex predator species shown valuable for environmental biomonitoring. This population depends on the Kopački rit Nature Park – the most important breeding sites. We assessed THg exposure, using nestling body feathers collected between 2014–2019 (n = 72), and potential dietary ecological sources, proxied by prey remains and stable isotope analysis. Results show THg concentrations vary significantly over the years, though not showing any time trend. Prey remains analysis shows nests with aquatic prey remains to exhibit higher THg concentrations (median: 7.57 μg g−1 dw; min – max: 6.00–13.16 μg g−1 dw) compared to those with terrestrial remains (median: 3.94 μg g−1 dw; min – max: 0.28–12.04 μg g−1 dw) or evidencing a mixed diet (median: 7.43 μg g−1 dw; min – max: 3.38–12.04 μg g−1 dw). Nests with a predominant aquatic diet show elevated lower δ13C and higher δ15N values, indicating agreement between both dietary approaches. The model selection reveals a combination of year and δ15N best explain the variability in feather THg concentrations. Complementing these predictors with a dietary descriptor based on prey remains results in a poorer model fit and lowered explanatory power, similar to sexing the nestlings. The observed body feather THg concentrations (median: 6.99 μg g−1 dw; min − max: 0.27 − 17.16 μg g−1 dw) exceeded putative biogeochemical background levels (5.00 μg g−1 dw) in 71% of the nestlings, though, did not seem to exceed a threshold at which detrimental physiological effects are expected (40 μg g−1 dw). Continued monitoring is warranted as the studied population is likely exposed to a larger cocktail of contaminants while resident-protected bird areas.
Due to developments in European legislation, several halogenated flame retardants are banned due to their toxicity, and the use of phosphor-based flame retardants in plastics is increasing. A revision of ammonium polyphosphate (APP) flame retardant revealed that it is an eye irritant and toxic, thus posing a health issue. Hence APP identification is needed for enabling safe recycling of plastic waste streams. Herein an industrial in-line method for quantitative estimation of APP in low density polyethylene (LDPE) and polypropylene (PP) is demonstrated, by using an industrial hyperspectral imaging system (955 to 1700 nm) and principal component analysis (PCA). Spectra of plastic samples with varying concentrations of APP were applied to build and calibrate a quantitative determination method. PCA and band area ratios (of selected bands) were made and fitted with continuous functions for concentration determination. The plastic samples were characterised by elemental analysis, attenuated total reflection, differential scanning calorimetry, and thermogravimetric analysis. The PCA model outperforms the band area ratio model and predicts APP concentrations between 24.3 and 1.5 wt% in LDPE (R2 = 0.98) and 20.0 and 1.7 wt% in PP (R2 = 0.97). Unknown samples with APP ranging from 23.7 to 2.7 wt% in LDPE and from 18.6 to 2.3 wt% in PP were predicted and correlated to the actual concentrations. The proposed approach is valuable for the plastic recyclers and waste management industries where inline concentration determination of flame retardants is key.
Aspects of Bayesian prediction have been addressed in previous chapters. In particular, Chaps. 7 and 9 show a Bayesian implementation of the spike and slab model for continuous and binary records, respectively, and illustrate how the marginal posterior distribution of validating mean squared errors can easily be computed in an McMC environment (pages 331 and 386).
We extend the classical Donaldson-Fujiki interpretation of the scalar curvature as moment map in Kähler geometry to the wider framework of locally conformally Kähler geometry.
Calendar systems adopted across the world are either solar, lunar or lunisolar, based on the movements of the sun, the moon, or both. The Gregorian (solar) calendars are considered as time references for modern computations. However, Vedic calendars, being lunisolar, can be more effective for the analysis of activities that depend on both celestial bodies. In this paper, we present VedicDateTime, an open-source framework that implements the Vedic calendar and provides conversions for Gregorian dates. Along with package details, we also provide two case studies that make use of the proposed package for time-series analysis. The objective of this paper is to motivate researchers to explore the potential of the Vedic calendar from the perspective of time series analysis.
Information-driven management and control of physical systems have emerged over the past decade in multiple industrial sectors and more recently also in construction. Such models are called “Digital twins”. However, in the domain of construction, and in particular in its specialty discipline safety, a digital twin (DT) remains rather undefined. Little or no consensus exists among researchers and practitioners of two essential aspects: (a) the connection between the physical reality of a construction site (the “physical” twin) and the corresponding computer model (the “digital” twin) and (b) the most effective selection and exploitation of real-life data for supporting safe design, planning, and execution of construction. This paper outlines the concept for a Digital Twin for Construction Safety (DTCS), defining four essential steps in the DT workflow: (1) safe design and planning for hazard prevention, (2) conformance checking for ensuring compliance, (3) risk monitoring and control for proactive prediction and alerting, and (4) continuous performance improvement for personalized- or project-based learning. DTCS should be viewed as a system-based approach enhancing the overall safety performance rather than exclusively integrating sensing information or safety knowledge in Building Information Modeling (BIM) for safety purposes. The result is an outline of our vision of the DTCS and a description of its modules in essential safety applications. Additionally, we point towards future research and development on this topic.
Technological reading and writing tools can help students with dyslexia improve their writing, but students do not use reading and writing functions as much as expected. However, research addressing relevant technological functions is scarce. This study explored the needs of writers with dyslexia and how technological writing tools developed for three Nordic languages meet these needs. Snowball sampling was used to identify different technological features, spellchecker, word prediction, auto‐correction, text‐to‐speech and speech‐to‐text functions available in nine widely used programmes were investigated. The results indicated that students with moderate spelling difficulties can now achieve accurate spellings using the most sophisticated spelling aids; however, most of these features require time and attention, and this can disturb writing fluency and hamper text production. The implication of this study is that the underlying conflict between spelling accuracy and writing fluency must be actively managed, which necessitates competence in the use of technological tools for both students and teachers in school. Also, further development of tools for scaffolding transcription must consider the dilemma of achieving both writing fluency and spelling accuracy. Further, the accuracy of the aid for students with severe spelling difficulties remains unclear and must be investigated.
Objectives To investigate the overall and type‐specific prenatal detection rates (DRs) of orofacial clefts in a national cohort in Denmark. Methods This study was based on data from the Danish Fetal Medicine Database (DFMD) and included all fetuses and children from singleton pregnancies diagnosed with an orofacial cleft pre‐ and/or postnatally between 2009 and 2018. The types of clefts included uni‐, bilateral or median cleft lip (CL); uni‐, bilateral or median cleft lip with secondary cleft palate (CLP); and cleft palate (CP). The clefts were grouped as cleft lip with and without cleft palate (CL(P)) or as all clefts. All cases with discordance between pre‐ and postnatal diagnoses were validated in the local patient files (Astraia). Cases with no prenatal validation of the postnatal diagnosis were marked as undetected. Cases with a strong prenatal presumption of a cleft were registered as prenatally detected. Terminations and intrauterine deaths were registered as true positives despite no autopsy had been performed. Live‐born cases with a prenatal diagnosis, but without a postnatal validation, were excluded. Results A total of 994 cases were included in the study. The prevalence of orofacial clefts was 1.7/1,000 births. There were no differences in baseline characteristics between the detected and undetected cases. The DR of CL(P) was 71.7% (95% CI 64.8;78.9) with an increase from 60.0% in 2009 to 73.0% in 2018 ( p =0.018). The type‐specific DRs for the entire period were: unilateral CL 56.4% (95% CI 45.0;67.6); unilateral CLP 76.6% (95% CI 71.7;82.9); bilateral CL 70.5% (95% CI 52.1;87.6); bilateral CLP 82.3% (95% CI 70.6;93.6); median CL 0.0% (0/6); median CLP 75.0% (3/4); and CP 3.3% (95% CI 0.6;5.7). A total of 20.9% (208/994) of the cases had associated findings, of which 33.2% (69/208) were genetic aberrations. Conclusion The DR of CL(P) has improved in Denmark in the last decade. The DR of CLP is high, with the highest DR in bilateral CLP. However, the prenatal detection of cleft palate remains a challenge. This article is protected by copyright. All rights reserved.
Stress is defined as a disruption of the body homeostasis in response to modest as well as perceived challenge. Two main physiological routes, the hypothalamic–pituitary–adrenal system (HPA) and the sympatho‐adrenomedullary system (SAM), aim to maintain or restore homeostasis by mutual interaction. SAM is quickly‐reacting as it primarily works through the nervous system—the sympathetic nervous system. In response to stress, signals are sent to activate the adrenal medulla which releases catecholamines (primarily adrenaline and norepinephrine). The catecholamines have a momentary effect on the body's organs that are prepared for a fight situation. At the same time, the stressor activates the HPA axis by signals from the brain causing secretion of the pituitary hormone adrenocorticotropic hormone (ACTH). ACTH acts on the adrenal cortex, which secretes glucocorticoids, including cortisol. Since HPA primarily works through hormones, the system is slightly slower than SAM and gives rise to a metabolic effect. While short‐term stress response is an adaptive and beneficial process, chronic or excessive stress can lead to a range of negative health outcomes including reproductive disorders and infertility. Several mechanisms have been proposed to explain the link between stress and reproduction. This includes in particular kisspeptin, which is closely related to reproduction, as it is a powerful stimulator of the Hypothalamic–pituitary–gonadal (HPG) system. The present review, through current knowledge in various male and female species, deals with the role of the SAM and the HPA, including the major action of kisspeptin and glucocorticoids that trigger the consequences of psychological or physiological stress on reproductive function.
The pleasurable urge to move to music (PLUMM) activates motor and reward areas of the brain and is thought to be driven by predictive processes. Dopamine in motor and limbic networks is implicated in beat‐based timing and music‐induced pleasure, suggesting a central role of basal ganglia (BG) dopaminergic systems in PLUMM. This study tested this hypothesis by comparing PLUMM in participants with Parkinson's disease (PD), age‐matched controls, and young controls. Participants listened to musical sequences with varying rhythmic and harmonic complexity (low, medium and high), and rated their experienced pleasure and urge to move to the rhythm. In line with previous results, healthy younger participants showed an inverted U‐shaped relationship between rhythmic complexity and ratings, with preference for medium complexity rhythms, while age‐matched controls showed a similar, but weaker, inverted U‐shaped response. Conversely, PD showed a significantly flattened response for both the urge to move and pleasure. Crucially, this flattened response could not be attributed to differences in rhythm discrimination and did not reflect an overall decrease in ratings. For harmonic complexity, PD showed a negative linear pattern for both the urge to move and pleasure while healthy age‐matched controls showed the same pattern for pleasure and an inverted U for the urge to move. This contrasts with the pattern observed in young healthy controls in previous studies, suggesting that both healthy aging and PD also influence affective responses to harmonic complexity. Together, these results support the role of dopamine within cortico‐striatal circuits in the predictive processes that form the link between the perceptual processing of rhythmic patterns and the affective and motor responses to rhythmic music.
Stress has a significant impact on reproductive health and fertility in both humans as well as various animal species. In particular, chronic stress can disrupt the delicate balance of the hormonal system that regulates reproductive function, leading to a variety of reproductive disorders and fertility issues. Beside the action of the hypothalamic‐pituitary‐adrenal (HPA) system and the sympatho‐adrenomedullary system (SAM), other subsequent mechanisms have been incriminated. Thus, stress has also been associated with increased prolactin level, resulting in an inhibition of the hypothalamo‐pituitary‐gonadal (HPG) system leading to several reproductive disorders. Thyroid function is inhibited during chronic stress, and therefore considered an important regulator of reproductive function. Thus, and in particular by interfering with the HPA system, stress‐induced immune dysregulation can have adverse effects on reproduction. In addition, oxidative stress and inflammation have been proposed as potential mechanisms by which chronic stress affects reproductive function. This is caused by an increase in reactive oxygen species (ROS) production that has a harmful effect on cells. Furthermore, inflammation can lead to tissue damage and scarring, which can affect fertility. The present review completes the complex mechanism linking stress and reproduction through the current knowledge in various animal species in a comparative point of view.
Herein, a convenient and operationally simple protocol for the ex‐situ generation of bis(trifluoromethyl)disulfide from the readily available and commercial Langlois reagent is reported. The one‐step synthesis of the toxic and volatile CF3SSCF3 is performed in a two‐chamber reactor with simple PPh3 and N‐bromosuccinimide as the activator, allowing for the safe handling and tandem utilization in direct trifluoromethylthiolation reactions. The versatility of the ex‐situ generated CF3SSCF3 is demonstrated in known electrophilic, nucleophilic, and a radical trifluoromethylthiolation reactions. Furthermore, the application of the CF3SSCF3 in a copper‐catalyzed cross‐coupling with boronic acids is disclosed, showing good to excellent yields of trifluoromethyl‐substituted aryl products, including pharmaceutically relevant molecules.
AI models that can recognize and understand the semantics of graphical user interfaces (GUIs) enable a variety of use cases ranging from accessibility to automation. Recent efforts in this domain have pursued the development of a set of foundation models: generic GUI understanding models that can be used off-the-shelf to solve a variety of GUI-related tasks, including ones that they were not trained on. In order to develop such foundation models, meaningful downstream tasks and baselines for GUI-related use cases will be required. In this paper, we present interactive link prediction as a downstream task for GUI understanding models and provide baselines as well as testing tools to effectively and efficiently evaluate predictive GUI understanding models. In interactive link prediction, the task is to predict whether tapping on an element on one screen of a mobile application (source element) navigates the user to a second screen (target screen). If this task is solved sufficiently, it can demonstrate an understanding of the relationship between elements and components across screens and enable various applications in GUI design automation and assistance. To encourage and support research on interactive link prediction, this paper contributes (1) a pre-processed large-scale dataset of links in mobile applications (18,830 links from 5,362 applications) derived from the popular RICO dataset, (2) performance baselines from five heuristic-based and two learning-based GUI understanding models, (3) a small-scale dataset of links in mobile GUI prototypes including ratings from an online study with 36 end-users for out-of-sample testing, and (4) a Figma plugin that can leverage link prediction models to automate and assist mobile GUI prototyping.
Purpose We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. Methods This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. Results Median cumulative administered activity of [¹⁷⁷Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3). Conclusion [¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. Trial registration ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.
The Farm to Fork (F2F) Strategy at the heart of the European Union’s Green Deal set out to create a “just transition” towards a sustainable food system, with benefits for all actors. We conducted a critical discourse analysis (CDA) to explore discourses around power in the food system and farmers’ position in the communication and implementation of the Farm to Fork Strategy. Discourse analysis encapsulates various scientific methodologies for deciphering the meaning behind the creation and communication of different forms of language and identify power dynamics, amongst other aspects. We identified two prior discourses in one of the objectives of the European Union’s new Common Agricultural Policy (2023-27). Our analysis found that the discourses, namely “rebalance power in food system” and “strengthening farmers’ position in value chains,” are marginalized in favour of an innovation-investment discourse, indicative of greater financialization and technologization based on techno-finances fixes in transforming the European Union agri-food system. We argue that entities representing agri-business interests have been influential in the policymaking process and voices representing smallholder and medium-sized farmers’ transformational discourses have been excluded.
Background In a true-natural cycle (t-NC), optimal progesterone (P4) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P4 levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P4 levels one day prior to warmed blastocyst transfer in t-NC. Method 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P4 (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P4 on FET − 1. Results Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P4 level was 12.9 ng/mL (IQR: 9.3–17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E2 and peak-P4 levels with P4 levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P4 levels on FET-1 day showed AUC of 0.70 (95%CI 0.61–0.79) for BMI (cut-off: 23.85 kg/m²), 0.71 (95%CI 0.61–0.80) for follicular phase peak-P4 levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59–0.77) for follicular phase peak-E2 levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72–0.88). The adjusted-odds ratio for having < 9.3 ng/mL P4 levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66–14.94). Conclusion The BMI, LUF, peak-E2, and peak-P4 levels are independent predictors of low serum P4 levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P4 on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes.
Modern societies produce vast amounts of digital data and merely keeping up with transmission and storage is difficult enough, but analyzing it to extract and apply useful information is harder still. Almost all research within healthcare data processing is concerned with formal clinical data. However, there is a lot of valuable but idle information in non-clinical data too; this information needs to be retrieved and activated. The present study combines state-of-the-art methods within distributed computing, text retrieval, clustering, and classification into a coherent and computationally efficient system that is able to clarify cancer patient trajectories based on non-clinical and freely available online forum posts. The motivation is: well informed patients, caretakers, and relatives often lead to better overall treatment outcomes due to enhanced possibilities of proper disease management. The resulting software prototype is fully functional and build to serve as a test bench for various text information retrieval and visualization methods. Via the prototype, we demonstrate a computationally efficient clustering of posts into cancer-types and a subsequent within-cluster classification into trajectory related classes. Also, the system provides an interactive graphical user interface allowing end-users to mine and oversee the valuable information.
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