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Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

Article originally published in the volume 60 issue 240 of Banca Nazionale del Lavoro Quarterly Review (also known as BNL Quarterly Review).

Lo scopo di questa nota è quello di presentare un modello analitico che dimostri come la presupposta contraddizione tra creazione di valore per gli azionisti e per i diversi portatori di interesse nei confronti dell’impresa (stakeholders) possa essere riconciliata. Nell’ambito di un modello stocastico vengono infatti utilizzati i più recenti e avanzati modelli di gestione aziendale basati sulla creazione di valore, sviluppati sia a livello accademico sia dalle più importanti società di consulenza, per provare, sotto determinate ipotesi, che la creazione di valore per gli shareholders e quella per gli stakeholders sono obiettivi solo apparentemente antitetici. The purpose of this note is to present an analytical model that demonstrates that the supposed contradiction between value creation for the shareholders and for the various stakeholders can be reconciled. Under a stochastic model are in fact used the latest and most advanced business models based on value creation, developed both in academia and by leading consulting firm, to prove, under certain assumptions, that the creation of value for the shareholders and for the stakeholders are objectives only apparently antithetical. JEL Codes: D21, G31, G32 Keywords: stakeholders, azionisti, shareholders, gestione aziendale

The academic debate on the theory of the firm has been monopolized for a long period by the contraposition between the shareholders model and the stakeholders model. Jensen (2001) introduced the concepts of "enlightened value maximization" and "enlightened stakeholders theory", recognizing the importance of the different constituencies for the maximization of the firm's market value. Masera (2006a) developed a "a quantitative synthesis of the enlightened stakeholders theory", supporting the idea that the total value of the firm is maximized when the management maximize both the remuneration of the shareholders and the efficiency and the satisfaction of the all the other stakeholders. In this paper, this thesis will be formalized by proposing a model in which a stochastic behavior for the most relevantvalue indicators is assumed. We will show that the model can be easily extended, allowing the simultaneous analysis of both value creation and capital structure problems. JEL Codes: D21, G32

Purpose: Lumbar interlaminar decompression with interspinous fixation is an established safe and effective treatment for spinal stenosis. Early maintenance of improvements in pain intensity and function are critical for durability of symptom relief. The purpose of this study was to investigate the efficacy of minimally invasive treatments for low back pain during the early period after treatment and their utility in setting the course for longer term success.Patients and Methods: This study utilized patient evaluations at 3- and 6-months following treatment and is part of an actively enrolling, institutional review board (IRB) approved, single-arm, multicenter, prospective, open-label 12-month study. Clinical efficacy was assessed primarily using the change from baseline in Oswestry Disability Index (ODI), Visual Analog Scale (VAS) of the back and leg pain during walking and standing, and Zurich Claudication Questionnaire (ZCQ), and secondarily using the Patient Global Impression of Change (PGIC) and Patient-Reported Outcomes Measurement Information System (PROMIS) 29 v2.1. The safety endpoints were the adverse events and reoperations or revisions at the index level(s).Results: At 6-month post-op, 76%, 62%– 64%, and 64% of patients demonstrated clinical meaningful, and statistically significant improvement in their pain as defined by ZCQ, VAS (back and leg), and ODI, respectively. In addition, 78% of patients noted improvement in PGIC. Two procedure-related adverse events were noted which fully resolved without surgical intervention.Conclusion: This 6-month interim analysis at 42% enrollment of patients was conducted to determine prolonged safety and efficacy of the interspinous fusion device. Our analysis showed a sustained improvement in clinical efficacy, and safety endpoints, when compared to the 3-months evaluations, across both interventional pain and neurosurgery specialties. [ABSTRACT FROM AUTHOR]

Abstract Immunological diseases are typically heterogeneous in clinical presentation, severity and response to therapy. Biomarkers of immune diseases often reflect this variability, especially compared to their regulated behaviour in health. This leads to a common difficulty that frustrates biomarker discovery and interpretation – namely, unequal dispersion of immune disease biomarker expression between patient classes necessarily limits a biomarker’s informative range. To solve this problem, we introduce dataset restriction, a procedure that splits datasets into classifiable and unclassifiable samples. Applied to synthetic flow cytometry data, restriction identifies biomarkers that are otherwise disregarded. In advanced melanoma, restriction finds biomarkers of immune-related adverse event risk after immunotherapy and enables us to build multivariate models that accurately predict immunotherapy-related hepatitis. Hence, dataset restriction augments discovery of immune disease biomarkers, increases predictive certainty for classifiable samples and improves multivariate models incorporating biomarkers with a limited informative range. This principle can be directly extended to any classification task.

Introduction: Bradykinesia, characterized by slowed movement, stands out as a primary symptom observed in individuals with Parkinson’s disease (PD). Nonetheless, there are instances where PD patients exhibit sudden and effective movements despite the presence of bradykinesia. This phenomenon, referred to as paradoxical kinesia, has remained a subject of interest for neuroscientists, who have struggled to unravel its underlying neural mechanisms for decades. Case Presentation: We describe a patient who is suffering from advanced PD. The patient has severe motor limitations, including difficulty rising from bed and walking, as well as cognitive decline and visual impairment. However, an interesting occurrence took place during a nightmare episode. Surprisingly, the patient was able to get out of bed and quickly run away from the perceived threat within the nightmare, without any assistance. Conclusion: This report presents the first documented case of paradoxical kinesia induced by nightmares in a patient with PD. This phenomenon raises questions about the neurological mechanisms involved, which are still not fully understood. Based on existing research conducted on both animal and human subjects, we propose that after processing the emotion of fear, the brain aversive system activates motor outputs to generate appropriate behavior. Thus, the brain aversive system converts the emotion of fear into action through projections from the inferior colliculus to motor-related areas such as the mesencephalic locomotor region, pontine nuclei, and substantia nigra.

Abstract Background Published data suggests that lockdowns during the COVID-19 pandemic may have negatively affected children’s weight development. This study aims to assess the prevalence of overweight and obesity after the COVID-19 lockdowns as well as anthropometric development among primary school children in the Rhein-Neckar Region, Germany. Methods In this cross-sectional study, schools were selected in cooperation with the local health authority to include different socioeconomic backgrounds. Participation was voluntary at school and individual level, requiring written informed consent from legal guardians. Study visits in schools were conducted between October 2021 and July 2022. Anthropometric data from nationally recommended medical examinations at 4 years (U8) and 5 years (U9), data on nutrition, physical activity, and socioeconomic data was collected using questionnaires. zBMI and weight category were calculated based on German reference data. Results 256 children with a mean age of 8.0 years (7.1–9.3 years) were included in the study. Most participants were from households with an above average income. 5.1% of the children were overweight, 4.7% were obese, 15.6% were underweight, and 74.6% were normal weight with a mean zBMI of -0.25 (SD 1.10), which is significantly lower than the mean zBMI of the German reference population (p

A comprehensive review, based on about 170 references, synthesizing research and development about Cratylia argentea, is presented to contribute to expand interest in its diffusion and use in animal production systems. The species has been widely evaluated, mainly in tropical America, with the objective to develop a shrub legume as an alternative to the fertile soils requiring Leucaena leucocephala and Gliricidia sepìum. The review comprises: (1) an illustrated description of the species, its biogeography and information on germplasm collections and genetic diversity; (2) synthesis and discussion of results from agronomic research, reproductive biology and seed production; (3) synthesis and discussion of results from research on nutritive value including secondary compounds, forage utilization and animal production. Particular strengths of the species are adaptation to the acid, low-fertility soils that prevail in the tropics, drought tolerance in subhumid climates with a pronounced dry season, and high nutritive value leading to increased animal production. Major shortcomings are slow establishment, labor demand in cut-and-carry systems and rapidly declining seed quality. A blend of two germplasm accessions was released as a commercial forage legume cultivar in Costa Rica and Colombia. Technology adoption issues are discussed and suggestions for future research presented.

A review synthesizing the research on the quality and use of Cratylia argentea forage to create incentives for its use in animal production systems in the tropics is presented. The species has been extensively evaluated, mainly in tropical America, to develop it as a shrub legume for infertile, acid soils as an alternative to Leucaena leucocephala and Gliricidia sepium that are not adapted to these soils. This review includes a synthesis and discussion of research findings with C. argentea forage on (1) nutritive value, including secondary compounds, (2) alternative uses in animal production systems, and (3) live weight gain and milk production. The strength of the species is its drought tolerance and high protein content that results in increased milk yield and liveweight gain when grazed in association with grasses, particularly in the dry season. Supplementation of fresh or ensiled cratylia to grazing animals usually results in increased carrying capacity of the pasture and milk yield for cows of medium to high genetic potential. Its deficiency is the low acceptability of fresh forage by animals with no previous experience and high demand for labor when used in cut and carry systems. The issue of low adoption is addressed and suggestions for future research are presented.

Abstract Background The aim of the investigation was to evaluate if a Class II malocclusion in adult patients can be successfully corrected by maxillary total arch distalization with interradicular mini-screws in combination with completely customized lingual appliances (CCLA). Methods Two patient groups were matched for age and gender to determine differences in the quality of final treatment outcome. The treatment results of 40 adult patients with a Class I malocclusion (Group 1) were compared with those of 40 adult patients with a moderate to severe Class II malocclusion (Group 2). All patients had completed treatment with a CCLA (WIN, DW Lingual Systems, Bad Essen, Germany) without overcorrection in the individual treatment plan defined by a target set-up. To compare the treatment results of the two groups, 7 measurements using the American Board of Orthodontics Model Grading System (ABO MGS) and linear measurements for anterior-posterior (AP) and vertical dimensions were assessed at the start of lingual treatment (T1), after debonding (T2B), and compared to the individual target set-up (T2A). Results A statistically significant AP correction (mean 4.5 mm, min/max 2.1/8.6, SD 1.09) was achieved in Group 2, representing 99% of the planned amount. The planned overbite correction was fully achieved in both the Class I and Class II groups. There was a statistically significant improvement in the ABO scores in both groups (Group 1: 39.4 to 17.7, Group 2: 55.8 to 17.1), with no significant difference between the two groups at T2B. 95% of the adult patients in Group 1 and 95% in Group 2 would meet the ABO standards after maxillary total arch distalization with a CCLA and interradicular mini-screws. Conclusions CCLAs in combination with interradicular mini-screws for maxillary total arch distalization can successfully correct moderate to severe Class II malocclusions in adult patients. The quality of the final occlusal outcome is high and the amount of the sagittal correction can be predicted by the individual target set-up.

Abstract Colour centres in silicon carbide emerge as a promising semiconductor quantum technology platform with excellent spin-optical coherences. However, recent efforts towards maximising the photonic efficiency via integration into nanophotonic structures proved to be challenging due to reduced spectral stabilities. Here, we provide a large-scale systematic investigation on silicon vacancy centres in thin silicon carbide membranes with thicknesses down to 0.25 μm. Our membrane fabrication process involves a combination of chemical mechanical polishing, reactive ion etching, and subsequent annealing. This leads to highly reproducible membranes with roughness values of 3–4 Å, as well as negligible surface fluorescence. We find that silicon vacancy centres show close-to lifetime limited optical linewidths with almost no signs of spectral wandering down to membrane thicknesses of ~0.7 μm. For silicon vacancy centres in thinner membranes down to 0.25 μm, we observe spectral wandering, however, optical linewidths remain below 200 MHz, which is compatible with spin-selective excitation schemes. Our work clearly shows that silicon vacancy centres can be integrated into sub-micron silicon carbide membranes, which opens the avenue towards obtaining the necessary improvements in photon extraction efficiency based on nanophotonic structuring.

Abstract Tepotinib is approved for the treatment of patients with non‐small‐cell lung cancer harboring MET exon 14 skipping alterations. While edema is the most prevalent adverse event (AE) and a known class effect of MET inhibitors including tepotinib, there is still limited understanding about the factors contributing to its occurrence. Herein, we apply machine learning (ML)‐based approaches to predict the likelihood of occurrence of edema in patients undergoing tepotinib treatment, and to identify factors influencing its development over time. Data from 612 patients receiving tepotinib in five Phase I/II studies were modeled with two ML algorithms, Random Forest, and Gradient Boosting Trees, to predict edema AE incidence and severity. Probability calibration was applied to give a realistic estimation of the likelihood of edema AE. Best model was tested on follow‐up data and on data from clinical studies unused while training. Results showed high performances across all the tested settings, with F1 scores up to 0.961 when retraining the model with the most relevant covariates. The use of ML explainability methods identified serum albumin as the most informative longitudinal covariate, and higher age as associated with higher probabilities of more severe edema. The developed methodological framework enables the use of ML algorithms for analyzing clinical safety data and exploiting longitudinal information through various covariate engineering approaches. Probability calibration ensures the accurate estimation of the likelihood of the AE occurrence, while explainability tools can identify factors contributing to model predictions, hence supporting population and individual patient‐level interpretation.

Summary: Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

The Sustainable Development Goals are far off track. The convergence of global threats such as climate change, conflict and the lasting effects of the COVID-19 pandemic—among others—call for better data and research evidence that can account for the complex interactions between these threats. In the time of polycrisis, global and national-level data and research evidence must address complexity. Viewed through the lens of ‘systemic risk’, there is a need for data and research evidence that is sufficiently representative of the multiple interdependencies of global threats. Instead, current global published literature seems to be dominated by correlational, descriptive studies that are unable to account for complex interactions. The literature is geographically limited and rarely from countries facing severe polycrisis threats. As a result, country guidance fails to treat these threats interdependently. Applied systems thinking can offer more diverse research methods that are able to generate complex evidence. This is achievable through more participatory processes that will assist stakeholders in defining system boundaries and behaviours. Additionally, applied systems thinking can draw on known methods for hypothesising, modelling, visualising and testing complex system properties over time. Application is much needed for generating evidence at the global level and within national-level policy processes and structures.

Objectives Administrative databases such as voter registries contain a wealth of information about a large proportion of a population. This is especially true when longitudinal information about individuals is available, such as changes in their names, addresses, or self-reported ethnic attributes. Apparent changes in ethnic attributes might be due to perceptions of majority evaluations of ethnic groups. In this project, we analysed snapshots of a publicly available US voter database from 2015 to 2022, exploring if and how recent presidential elections impacted changes in voters' self-reported ethnic attributes. Approach Using bi-monthly snapshots of a publicly available US voter database from 2015 to 2022, we generated cohorts by linking active voters during seven twelve-month periods (2015/16 to 2021/22). These seven time periods included one mid-term and two presidential elections, and four control time spans before, between, and after these elections. We compared changes in self-reported ethnic attributes of voters during the times of elections versus the control time periods. Results Preliminary results reveal a substantial change to self-reported ethnic attributes during the periods leading to an election. A majority of such changes are by individuals from a specific ethnic group choosing not to report an ethnicity, an indication of their preference to not disclose ethnicity-related sensitive information. Conclusions We have shown how a publicly available voter database can be used to explore how self-reported ethnic attributes are modified by individual voters over time, and how the prevalence of such changes is influenced by political events such as presidential elections.

Objectives It has been shown that record linkage methods can induce bias in resulting datasets since the linkage quality may differ between ethno-racial groups. In this project, we used publicly available voter databases to investigate whether ethno-racial attributes can influence the similarities calculated using approximate string comparison functions on voters' names. Approach We used 11 annual snapshots of a publicly available US voter database between 2011 and 2021 with uniquely identifiable voter data. We extracted pairs of the same voter’s first and last name values from two consecutive snapshots where these values differ. We calculated string similarities and created similarity histograms for each of the available ethno-racial categories, and other sociodemographics variables such as gender and age. We characterized common patterns of name disagreements by ethno-racial groups and compared the shapes of these histograms using cumulative density distributions. Preliminary Results Across the 10 snapshot pairs, eligible voters with non-missing first and last names are included (N2011/2012 = 6,193,001, N2020/2021 = 7,852,763), describing 124,009 first name changes and 485,807 last name changes. Results will be presented as a series of density plots. Using Jaro-Winkler similarity scores of 0.7, 0.8 and 0.9 as threshold, we examined whether match rates differ by ethno-racial categories. Conclusions and Implications Using the same string similarity function on names of individuals of different ethno-racial groups may lead to different distributions of the resulting similarity values. Understanding the patterns of ethno-racial-based name changes in your particular dataset is crucial on selecting linkage parameters that would minimise ethno-racial bias.

Objectives Data linkage is the process of matching records that refer to the same entities (often people) across databases. In applications such as health research or government services, the databases to be linked are often sensitive and cannot be shared between organisations. Privacy-preserving record linkage (PPRL) aims to overcome this challenge by facilitating the comparison of encoded or encrypted records without having to share sensitive data. Most existing PPRL techniques are based on heuristics and they have limitations in the privacy protection they offer, such as being vulnerable to certain cryptanalysis attacks. Furthermore, existing PPRL methods have multiple parameters, which, if not set properly by the user, can result in sub-optimal linkage quality and reduced privacy protection. Approach We present a novel PPRL method that uses random reference q-gram sets to generate bit-arrays that represent sensitive values. Our method has a single parameter to be set by the user that trades scalability with linkage quality and privacy protection. All other parameters are either data-driven or have strong bounds based on this user parameter. Results We conceptually analyse our method and conduct experiments on multiple databases. The results demonstrate that our method provides high linkage quality and strong privacy protection while being scalable to link very large databases. Conclusion Our novel PPRL method provides high linkage quality, scalability, and improved privacy protection compared to existing PPRL methods such as Bloom filter encoding. A major advantage of our method is that it requires a single parameter to be set by the user.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) following oral or intravenous chemotherapy often results in neuropathic pain, accompanied by symptoms such tingling, burning and hypersensitivity to stimuli, with a notable decline in quality of life (QoL). Effective therapies for CIPN are lacking, with a high demand for analgesics to address this issue. The QUCIP study aimed to assess the effectiveness of high concentration (179 mg) capsaicin patch (HCCP) in alleviating neuropathic pain and associated symptoms in breast cancer patients with confirmed CIPN.MethodsQUCIP is a prospective, multi-center observational study spanning 36 weeks with up to three HCCP treatments. Initial treatment (visit V0) was followed by two telephone contacts (T1, T2) and subsequent face-to-face visits every 12 weeks or upon retreatment (visits V1–V3). 73 female patients with painful CIPN post neoadjuvant/adjuvant breast cancer therapy were enrolled. Primary endpoint was the reduction of neuropathic pain symptom score (painDETECT®). Secondary endpoints included improvements in CIPN-specific QoL (QLQ-CIPN20), reductions in pain intensity (numeric pain rating scale, NPRS), and achievement of ≥ 30% and ≥ 50% pain reduction.ResultsMedian age was 61 years, with 52.0% of patients experiencing peripheral neuropathic pain for > 1 year (> 2 years: 34.2%). The painDETECT® score significantly decreased from baseline (19.71 ± 4.69) to 15.80 ± 6.20 after initial treatment (p < 0.0001) and continued to decrease at follow-up visits. The NPRS indicated significant pain intensity reduction at each time point, particularly pronounced in patients receiving three HCCP treatments. Clinically significant pain relief of ≥ 30% increased from 25.0% at week 4 (T2) to 36.2%, 43.5%, and 40.0% at weeks 12 (V1), 24 (V2), and 36 (V3), respectively. The percentage of patients achieving pain relief of ≥ 50% increased from 14.7% at T2 to 15.5%, 21.7% and 32.5% at V1, V2 and V3, respectively. Patients further reported a significant improvement in their CIPN-related QoL throughout the study. Adverse drug reactions (ADRs) mainly included application site reactions.ConclusionIn this study, HCCP shows benefit in managing CIPN in real-world settings. The data demonstrate a sustained and progressive reduction in neuropathic pain and symptomatology, confirming the clinical benefit of repeated treatment observed in former clinical trials. HCCP treatment has also the potential to significantly improve the QoL associated with CIPN. The safety profile of HCCP was confirmed, supporting its use in clinical practice.

Pinpointing elements on large tactile surfaces is challenging for individuals with blindness and visual impairment (BVI) seeking to access two-dimensional (2D) information. This is particularly evident when using 2D tactile readers, devices designed to provide 2D information using static tactile representations with audio explanations. Traditional pinpointing methods, such as sighted assistance and trial-and-error, are limited and inefficient, while alternative pinpointing user interfaces (UI) are still emerging and need advancement. To address these limitations, we develop three distinct navigation UIs using a user-centred design approach: Sonar (proximity-radar sonification), Voice (direct clock-system speech instructions), and Sonoice, a new method that combines elements of both. The navigation UIs were incorporated into the Tactonom Reader device to conduct a trial study with ten BVI participants. Our UIs exhibited superior performance and higher user satisfaction than the conventional trial-and-error approach, showcasing scalability to varied assistive technology and their effectiveness regardless of graphic complexity. The innovative Sonoice approach achieved the highest efficiency in pinpointing elements, but user satisfaction was highest with the Sonar approach. Surprisingly, participant preferences varied and did not always align with their most effective strategy, underscoring the importance of accommodating individual user preferences and contextual factors when choosing between the three UIs. While more extensive training may reveal further differences between these UIs, our results emphasise the significance of offering diverse options to meet user needs. Altogether, the results provide valuable insights for improving the functionality of 2D tactile readers, thereby contributing to the future development of accessible technology.

Key Clinical Message Negative pressure wound therapy (NPWT) aided in the management of complex soft tissue injury in a 14‐year‐old girl by managing moisture, reducing oedema, and stimulating wound granulation less than 2 months after the accident and prepared the skin for skin grafting, thus successfully saving the limb. Abstract This case study describes the use of a tubular bandage encompassing the whole limb to deliver successful NPWT in the treatment and reconstruction of extensive soft tissue damage extending from the right lower extremity to the hip in a 14‐year‐old female.

BackgroundAge reportedly affects headache prevalence differently in boys and girls. However, little empirical data exists regarding pediatric headache prevalence and headache-related burden in children and adolescents according to age and sex. In the present study, we considered age and sex while evaluating the distribution, characteristics, and impairment of primary headache disorders at a pediatric headache center in Germany.MethodsMedical records of children and adolescents attending the headache clinic of the Interdisciplinary Pain Center of the Carl Gustav Carus University Hospital in Dresden during the period 2015–2022 were retrospectively grouped and analyzed depending on age (< or ≥14 years) and sex.ResultsThe study population consisted of 652 children and adolescents, aged between 3 and 18 years. Almost two-thirds of the patients (≈60%) were females, and almost two-thirds of these females (58%) were ≥14 years of age. Generally, the most prevalent headache diagnoses as defined by the International Classification of Headache Disorders 3rd edition were episodic migraine without aura and the combination of tension-type headache and episodic migraine with or without aura i.e., mixed-type headache (each ≈27%). In the younger group (

Abstract Apart from seizure freedom, the presence of comorbidities related to neurological, cardiovascular, or psychiatric disorders is the largest determinant of a reduced health‐related quality of life in people with epilepsy (PwE). However, comorbidities are often underrecognized and undertreated, and clinical management of comorbid conditions can be challenging. The focus of a comprehensive treatment regimen should maximize seizure control while optimizing clinical management of treatable comorbidities to improve a person's quality of life and overall health. A panel of four European epileptologists with expertise in their respective fields of epilepsy‐related comorbidities combined the latest available scientific evidence with clinical expertise and collaborated to provide consensus practical advice to improve the identification and management of comorbidities in PwE. This review provides a critical evaluation for the diagnosis and management of sleep–wake disorders, cardiovascular diseases, cognitive dysfunction, and depression in PwE. Whenever possible, clinical data have been provided. The PubMed database was the main search source for the literature review. The deleterious pathophysiological processes underlying neurological, cardiovascular, or psychiatric comorbidities in PwE interact with the processes responsible for generating seizures to increase cerebral and physiological dysfunction. This can increase the likelihood of developing drug‐resistant epilepsy; therefore, early identification of comorbidities and intervention is imperative. The practical evidence‐based advice presented in this article may help clinical neurologists and other specialist physicians responsible for the care and management of PwE.

Abstract Most general population web surveys are based on online panels maintained by commercial survey agencies. Many of these panels are based on non-probability samples. However, survey agencies differ in their panel selection and management strategies. Little is known if these different strategies cause differences in survey estimates. This paper presents the results of a systematic study designed to analyze the differences in web survey results between agencies. Six different survey agencies were commissioned with the same web survey using an identical standardized questionnaire covering factual health items. Five surveys were fielded at the same time. A calibration approach was used to control the effect of demographics on the outcome. Overall, the results show differences between probability and non-probability surveys in health estimates, which were reduced but not eliminated by weighting. Furthermore, the differences between non-probability surveys before and after weighting are larger than expected between random samples from the same population.

Abstract With Wilson quarks, on-shell O(a) improvement of the lattice QCD action is achieved by including the Sheikholeslami-Wohlert term and two further operators of mass dimension 5, which amount to a mass-dependent rescaling of the bare parameters. We here focus on the rescaled bare coupling, g ~ 0 2 = g 0 2 1 + b g a m q $$ {\tilde{g}}_0^2={g}_0^2\left(1+{b}_{\textrm{g}}a{m}_{\textrm{q}}\right) $$ , and the determination of b g g 0 2 $$ {b}_{\textrm{g}}\left({g}_0^2\right) $$ which is currently only known to 1-loop order of perturbation theory. We derive suitable improvement conditions in the chiral limit and in a finite space-time volume and evaluate these for different gluonic observables, both with and without the gradient flow. The choice of β-values and the line of constant physics are motivated by the ALPHA collaboration’s decoupling strategy to determine α s (m Z ) [1]. However, the improvement conditions and some insight into systematic effects may prove useful in other contexts, too.

Abstract The Ca2+ activated Cl− channel TMEM16A (anoctamin 1; ANO1) is expressed in secretory epithelial cells of airways and intestine. Previous studies provided evidence for a role of ANO1 in mucus secretion. In the present study we investigated the effects of the two ANO1-inhibitors niclosamide (Niclo) and benzbromarone (Benz) in vitro and in vivo in mouse models for cystic fibrosis (CF) and asthma. In human CF airway epithelial cells (CFBE), Ca2+ increase and activation of ANO1 by adenosine triphosphate (ATP) or ionomycin was strongly inhibited by 200 nM Niclo and 1 µM Benz. In asthmatic mice airway mucus secretion was inhibited by intratracheal instillation of Niclo or Benz. In homozygous F508del-cftr mice, intestinal mucus secretion and infiltration by CD45-positive cells was inhibited by intraperitoneal injection of Niclo (13 mg/kg/day for 7 days). In homozygous F508del-cftr rats intestinal mucus secretion was inhibited by oral application of Benz (5 mg/kg/day for 60 days). Taken together, well tolerated therapeutic concentrations of niclosamide and benzbromarone corresponding to plasma levels of treated patients, inhibit ANO1 and intracellular Ca2+ signals and may therefore be useful in inhibiting mucus hypersecretion and mucus obstruction in airways and intestine of patients suffering from asthma and CF, respectively.

In rats decreased bioavailability of nitric oxide induces oxidative stress and right heart failure. Oxidative stress can activate matrix metalloproteinase-2 (MMP2). We addressed the question whether increasing oxidative defense by administration of the SOD mimetic Tempol or direct inhibition of MMP2 activity by SB-3CT mitigates right heart failure. Rats received l-NAME for four weeks and during week three and four treatment groups received either Tempol or SB-3CT in addition. After four weeks heart function was analyzed by echocardiography, organ weights and expression of NPPB and COL1A1 were analyzed, oxidative stress was monitored by DHE-staining and MMP2 activity was quantified by proteolytic auto-activation, zymography, and troponin I degradation. l-NAME induced oxidative stress and MMP2 activity stronger in the right ventricle than in the left ventricle. Troponin I, a MMP2 substrate, was degraded in right ventricles. Tempol reduced oxidative stress and preferentially affected the expression of fibrotic genes (i.e. COL1A1) and fibrosis. Tempol and SB-3CT mitigated right but not left ventricular hypertrophy. Neither SB-3CT nor Tempol alone strongly improved right ventricular function. In conclusion, both MMP2 activity and oxidative stress contribute to right ventricular failure but neither is MMP2 activation linked to oxidative stress nor does oxidative stress and MMP2 activity have common targets.

IntroductionPostmortem computed tomography (pmCT) prior to forensic autopsy has become increasingly important in recent decades, especially in forensic documentation of single injuries, injury patterns, and causes of death. Postmortem decomposition gas formation can also be detected in pmCT scans, which might affect cochlear implant research in postmortem human temporal bones (TBs).Material and methodsFifty non-putrefied hanging fatalities within a 2-year period (January 2017 to December 2019) were included with 100 TBs. Each body underwent whole-body pmCT prior to forensic autopsy. PmCT scans were analyzed with respect to the presence of intracochlear gas despite the lack of putrefaction at autopsy by an experienced fellow neurotologist.ResultsPmCT revealed gas formation in two individuals despite the lack of head trauma and putrefaction at postmortem examination and autopsy. Both individuals showed enclosed gas in the vestibule and the cochlea on both sides.DiscussionIntracochlear gas formation, most likely related to decomposition, may occur despite the lack of putrefaction at postmortem examination and autopsy and can be detected by pmCT. This finding seems to be rather rare in non-traumatic death cases but might affect cochlear pressure research in postmortem human TB.

PurposeNeuroglial tumors are frequently associated with pharmacorefractory epilepsies. However, comprehensive knowledge about long-term outcomes after epilepsy surgery and the main prognostic factors for outcome is still limited. We sought to evaluate long-term outcomes and potential influencing factors in a large cohort of patients who underwent surgery for neuroglial tumors in a single-center setting.MethodsThe study analyzed the outcomes of 107 patients who underwent epilepsy surgery for neuroglial tumors between 2001 and 2020 at the Department of Epileptology, University Hospital Bonn, in Germany. The outcomes were evaluated using Engel classification. Differences in outcome related to potential prognostic factors were examined using the Chi2-test, Fisher’s exact test and sign test. Additionally, stepwise logistic regression analysis was employed to identify independent prognostic factors.ResultsComplete seizure freedom (Engel Class IA) was achieved in 75% of the operated patients at 12 months, and 56% at the last follow-up visit (70.4 ± 6.2 months, median: 40 months). Completeness of resection was a crucial factor for both 12-month follow-up outcomes and the longest available outcomes, whereas lobar tumor localization, histology (ganglioglioma vs. dysembryoplastic neuroepithelial tumor), history of bilateral tonic–clonic seizures prior to surgery, invasive diagnostics, side of surgery (dominant vs. non-dominant hemisphere), age at epilepsy onset, age at surgery, and epilepsy duration did not consistently impact postsurgical outcomes. Among temporal lobe surgeries, patients who underwent lesionectomy and lesionectomy, including hippocampal resection, demonstrated similar outcomes.ConclusionNeuroglial tumors present as excellent surgical substrates in treating structural epilepsy. To achieve an optimal postsurgical outcome, a complete lesion resection should be pursued whenever possible.

STUDY AIMS: During the COVID-19 pandemic, there was increasing pressure to be vaccinated to prevent further spread of the virus and improve outcomes. At the same time, part of the population expressed reluctance to vaccination, for various reasons. Only a few studies have compared the perceptions of vaccinated and non-vaccinated patients being treated in hospitals for COVID-19. Our aim was to investigate the association between vaccination status and perceived healthcare-associated discrimination in patients with COVID-19 receiving hospital treatment. METHODS: Adult patients presenting to the emergency department or hospitalised for inpatient care due to or with COVID-19 from 1 June to 31 December 2021 in two Swiss hospitals were eligible. The primary endpoint was patients’ perceived healthcare-associated discrimination, measured with the Discrimination in Medical Settings (DMS) scale. Secondary endpoints included different aspects of perceived quality of care and symptoms of psychological distress measured with the Hospital Anxiety and Depression Scale. RESULTS: Non-vaccinated patients (n = 113) had significantly higher DMS scores compared to vaccinated patients (n = 80) (mean: 9.54 points [SD: 4.84] vs 7.79 points [SD: 1.85]; adjusted difference: 1.18 [95% CI: 0.04–2.33 points]) and 21 of 80 vaccinated patients felt discriminated against vs 54 of 113 non-vaccinated patients (adjusted OR: 2.09 [95% CI: 1.10–3.99 ]). Non-vaccinated patients reported lower scores regarding respectful treatment by the nursing team (mean: 8.39 points [SD: 2.39] vs 9.30 points [SD: 1.09]; adjusted difference: –0.6 [95% CI: -1.18 – –0.02 points]). CONCLUSION: We found an association between vaccination status and perceived healthcare-associated discrimination. Healthcare workers should act in a professional manner regardless of a patient’s vaccination status; in doing so, they might prevent the creation of negative perceptions in patients.

BackgroundWith the prevalence of burnout among surgeons posing a significant threat to healthcare outcomes, the mental toughness of medical professionals has come to the fore. Mental toughness is pivotal for surgical performance and patient safety, yet research into its dynamics within a global and multi-specialty context remains scarce. This study aims to elucidate the factors contributing to mental toughness among surgeons and to understand how it correlates with surgical outcomes and personal well-being.MethodsUtilizing a cross-sectional design, this study surveyed 104 surgeons from English and German-speaking countries using the Mental Toughness Questionnaire (MTQ-18) along with additional queries about their surgical practice and general life satisfaction. Descriptive and inferential statistical analyses were applied to investigate the variations in mental toughness across different surgical domains and its correlation with professional and personal factors.ResultsThe study found a statistically significant higher level of mental toughness in micro-surgeons compared to macro-surgeons and a positive correlation between mental toughness and surgeons' intent to continue their careers. A strong association was also observed between general life satisfaction and mental toughness. No significant correlations were found between the application of psychological skills and mental toughness.ConclusionMental toughness varies significantly among surgeons from different specialties and is influenced by professional dedication and personal life satisfaction. These findings suggest the need for targeted interventions to foster mental toughness in the surgical community, potentially enhancing surgical performance and reducing burnout. Future research should continue to explore these correlations, with an emphasis on longitudinal data and the development of resilience-building programs.