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Acetamiprid (ACE) and imidacloprid (IMI) are insecticides of global importance and are used as spray and watering agents for ornamental plants to control biting and sucking insects or as topical medications on pets to remove and control fleas. Human biomonitoring data on ACE and IMI exposures when applying these products are limited. We investigated exposures to ACE and IMI in male volunteers after the domestic application of either an ACE-containing agent or an IMI-containing spot-on medication. Complete and consecutive urine samples were collected for up to 56 h after application. Urine samples were analyzed for ACE, IMI, and their respective metabolites (N-desmethyl-ACE, IMI-olefin, and sum of 4−/5-hydroxy-IMI) by liquid chromatography–tandem mass spectrometry. Fairly uniform concentrations of N-desmethyl-ACE could be observed before and after orchid treatment, so that an ACE exposure associated with orchid treatment can most likely be excluded. In contrast, after the application of the IMI-containing medication, elevated concentrations of IMI, 4−/5-hydroxy-IMI, and IMI-olefin were quantified in urine samples post-20 h with maximum concentrations of 3.1, 14.9, and 8.0 μg/g creatinine, respectively, well above general background levels. Nevertheless, the IMI intake (10.6 μg/kg bw), calculated from the excreted amounts, was around five times below the current European acceptable daily intake. Based on the case results here, household exposures to ACE and IMI after spray treatment of ornamental plants and anti-flea treatment of dogs can be regarded as low and safe. However, people regularly applying neonicotinoid-containing formulations, such as professional gardeners and employees in animal shelters, should be studied in more detail.

Invariant natural killer T (iNKT) cells are a unique T lymphocyte population expressing semi-invariant T cell receptors (TCRs) that recognise lipid antigens presented by CD1d. iNKT cells exhibit potent anti-tumour activity through direct killing mechanisms and indirectly through triggering the activation of other anti-tumour immune cells. Because of their ability to induce potent anti-tumour responses, particularly when activated by the strong iNKT agonist αGalCer, they have been the subject of intense research to harness iNKT cell-targeted immunotherapies for cancer treatment. However, despite potent anti-tumour efficacy in pre-clinical models, the translation of iNKT cell immunotherapy into human cancer patients has been less successful. This review provides an overview of iNKT cell biology and why they are of interest within the context of cancer immunology. We focus on the iNKT anti-tumour response, the seminal studies that first reported iNKT cytotoxicity, their anti-tumour mechanisms, and the various described subsets within the iNKT cell repertoire. Finally, we discuss several barriers to the successful utilisation of iNKT cells in human cancer immunotherapy, what is required for a better understanding of human iNKT cells, and the future perspectives facilitating their exploitation for improved clinical outcomes.

ObjectivesWe developed and tested a deep learning (DL) framework applicable to color Doppler echocardiography for automatic detection and quantification of atrial septal defects (ASDs).BackgroundColor Doppler echocardiography is the most commonly used non-invasive imaging tool for detection of ASDs. While prior studies have used DL to detect the presence of ASDs from standard 2D echocardiographic views, no study has yet reported automatic interpretation of color Doppler videos for detection and quantification of ASD.MethodsA total of 821 examinations from two tertiary care hospitals were collected as the training and external testing dataset. We developed DL models to automatically process color Doppler echocardiograms, including view selection, ASD detection and identification of the endpoints of the atrial septum and of the defect to quantify the size of defect and the residual rim.ResultsThe view selection model achieved an average accuracy of 99% in identifying four standard views required for evaluating ASD. In the external testing dataset, the ASD detection model achieved an area under the curve (AUC) of 0.92 with 88% sensitivity and 89% specificity. The final model automatically measured the size of defect and residual rim, with the mean biases of 1.9 mm and 2.2 mm, respectively.ConclusionWe demonstrated the feasibility of using a deep learning model for automated detection and quantification of ASD from color Doppler echocardiography. This model has the potential to improve the accuracy and efficiency of using color Doppler in clinical practice for screening and quantification of ASDs, that are required for clinical decision making.

The recent technologies rise today as a tool of significant importance today, especially in the educational context. In this sense, Augmented Reality (AR) is a technology that is achieving a greater presence in educational centers in the last decade. However, Augmented Reality has not been explored in depth at the Secondary Education stage. Due to this, it is essential to analyze and concentrate the scientific research developed around this educational technology at that stage. Therefore, the aim of this research is to describe the influence that Augmented Reality shows on the motivation and academic performance of students in the Secondary Education stage. In relation to the methodology, a systematic review of the literature has been conducted using the Kitchenham protocol, where several factors have been analyzed, such as subjects, activities, and electronic implementation devices, together with the effects on motivation and student's academic performance. The Scopus and Web of Science (WoS) databases have been used to search for scientific papers, with a total of 344 investigations being analyzed between 2012 and 2022. The methodological stages considered were the formulation of research questions, the choice of data sources, search strategies, inclusion and exclusion criteria and quality assessment, and finally, data extraction and synthesis. The results obtained have shown that the use of AR in the classroom provides higher levels of motivation, reflected by factors such as attention, relevance, confidence, and satisfaction, and reflects better results in the tests carried out on the experimental groups compared to the control groups, which means an improvement in the academic performance of students. These results supply a fundamental theoretical basis, where the different teachers should be supported for the incorporation of AR in the classroom, since how this educational technology has been shown offers great opportunities. Likewise, the development of research in areas not so addressed can further clarify the generality of AR based on its influence on learning. In addition, the fields of natural sciences and logical-mathematical have been the most addressed, managing to implement their contents through object modeling. In short, this research highlights the importance of incorporating Augmented Reality into all areas and educational stages, since it is a significant improvement in the teaching and learning process.

Objective: Investigation of lymph fluid dynamics in thoracic duct during central venous pressure elevation.Background: Lymphatic flow is affected by elevated central venous pressure (CVP) in congestive heart failure. The changes of thoracic duct (TD) lymph flow have not been studied chronically in the setting of elevated CVP. This study is to investigate fluid dynamics and remodeling of the TD in the elevated CVP animal model.Methods: A flow probe was implanted on the swine TD (n = 6) and tricuspid regurgitation (TR) was created by cutting tricuspid chordae percutaneously. Six swine were used as control group animals. The TD flow was measured for 2 weeks (baseline) before TR and 4 weeks postop-TR surgery. Arterial pressure and CVP were measured. The pressure and flow in the TD were measured percutaneously. Histological and morphological analyses were performed.Results: TR resulted in an increase in CVP from 4.2 ± 2.6 to 10.1 ± 4.3 mmHg (p < 0.05). The lymph flow in the TD increased from 0.78 ± 1.06 before TR to 8.8 ± 4.8 ml/min (p < 0.05) 2 days post-TR and remained plateau for 4 weeks, i.e., the TD flow remained approximately 8–11 fold its baseline. Compared to the 8.1 ± 3.2 mmHg control group, the TD average pressures at the lymphovenous junction increased to 14.6 ± 5.7 mmHg in the TR group (p < 0.05). The TD diameter and wall thickness increased from 3.35 ± 0.37 mm and 0.06 ± 0.01 mm in control to 4.32 ± 0.57 mm and 0.26 ± 0.02 mm (p < 0.05) in the TR group, respectively.Conclusion: The elevated CVP results in a significant increase in TD flow and pressure which causes the TD’s outward remodeling and thickening. Our study implicates that the outward remodeling may result in the TD valve incompetence due to failure coaptation of leaflets.

ObjectiveTo compare the performance of a newly developed deep learning (DL) framework for automatic detection of regional wall motion abnormalities (RWMAs) for patients presenting with the suspicion of myocardial infarction from echocardiograms obtained with portable bedside equipment versus standard equipment.BackgroundBedside echocardiography is increasingly used by emergency department setting for rapid triage of patients presenting with chest pain. However, compared to images obtained with standard equipment, lower image quality from bedside equipment can lead to improper diagnosis. To overcome these limitations, we developed an automatic workflow to process echocardiograms, including view selection, segmentation, detection of RWMAs and quantification of cardiac function that was trained and validated on image obtained from bedside and standard equipment.MethodsWe collected 4,142 examinations from one hospital as training and internal testing dataset and 2,811 examinations from other hospital as the external test dataset. For data pre-processing, we adopted DL model to automatically recognize three apical views and segment the left ventricle. Detection of RWMAs was achieved with 3D convolutional neural networks (CNN). Finally, DL model automatically measured the size of cardiac chambers and left ventricular ejection fraction.ResultsThe view selection model identified the three apical views with an average accuracy of 96%. The segmentation model provided good agreement with manual segmentation, achieving an average Dice of 0.89. In the internal test dataset, the model detected RWMAs with AUC of 0.91 and 0.88 respectively for standard and bedside ultrasound. In the external test dataset, the AUC were 0.90 and 0.85. The automatic cardiac function measurements agreed with echocardiographic report values (e. g., mean bias is 4% for left ventricular ejection fraction).ConclusionWe present a fully automated echocardiography pipeline applicable to both standard and bedside ultrasound with various functions, including view selection, quality control, segmentation, detection of the region of wall motion abnormalities and quantification of cardiac function.

Open Education (OE) opens up learning opportunities to, potentially, every person in the world. Additionally, it allows teachers, researchers, and practitioners to find, share, reuse, and improve existing resources under a dependable legal framework. Aiming to spread and foster the introduction of open policies in Higher Education (HE) institutions, the gamified interactive learning experience Catch the Open! was developed. Catch the Open! targets HE educators who wish to learn, or who wish to deepen their existing knowledge, about OE and Open Educational Practices (OEP). Within the gamified learning experience, the user becomes an educator, Alex, the game character, who receives a task from the Rector: to investigate how to best include OE and OEP in teaching and learning practice within the institution. Alex proceeds to explore and gather information in a web-based 2D virtual HE institution where students, colleagues, and guest researchers will help her to develop a comprehensive understanding of OE and the practical application of OEP. The educational content within Catch the Open! is underpinned by an OE competences framework for HE educators, developed in a previous phase of the Erasmus+ OpenGame project. In this paper, the design process to link pedagogical and technological approaches, which results in the Catch the Open! gamified web-based interactive application, is presented as well as the application itself. Moreover, two phases of piloting with 153 HE educators from six different HE institutions are presented. The obtained findings showed that the gamified environment helped in learning about OE. On the other hand, learners also suggested several improvement aspects of the gamified environment, such as the length of finishing a learning mission while playing.

Sporadic efforts have been made to introduce computational thinking methods into K-12 education in Palestine, but these have been held back by the challenging educational environment. However, a recent in-service training initiative, funded and organized by the Ministry or Education of Palestine, constitutes a significant effort to embed computational thinking in K-12 practice. The middle school teachers who participated in the training course were invited to participate in the present study, and 38 did so. A qualitative approach involving both interviews with teachers and classroom observations was used in data collection. All the teachers agreed to be observed in their classrooms, while 20 of the 38 also agreed to participate in the interviews. The findings showed that teachers of a range of topics, including social sciences and languages, employed computational thinking skills in teaching their students, but they were confronted by a number of challenges, including technical infrastructure and support, and a lack of time to prepare CT classes and space in the curriculum to deliver them. The results indicate that the most appropriate action to support teachers’ delivery of CT would be to provide peer exchanges and expert coaching in the integration of CT in the curriculum.

ObjectiveExposure to high altitudes represents physiological stress that leads to significant changes in cardiovascular properties. However, long-term cardiovascular adaptions to high altitude migration of lowlanders have not been described. Accordingly, we measured changes in cardiovascular properties following prolonged hypoxic exposure in acclimatized Han migrants and Tibetans.MethodsEchocardiographic features of recently adapted Han migrant (3–12 months, n = 64) and highly adapted Han migrant (5–10 years, n = 71) residence in Tibet (4,300 m) using speckle tracking echocardiography were compared to those of age-matched native Tibetans (n = 75) and Han lowlanders living at 1,400 m (n = 60).ResultsShort-term acclimatized migrants showed increased estimated pulmonary artery systolic pressure (PASP) (32.6 ± 5.1 mmHg vs. 21.1 ± 4.2 mmHg, p < 0.05), enlarged right ventricles (RVs), and decreased fractional area change (FAC) with decreased RV longitudinal strain (−20 ± 2.8% vs. −25.5 ± 3.9%, p < 0.05). While left ventricular ejection fraction (LVEF) was preserved, LV diameter (41.7 ± 3.1 mm vs. 49.7 ± 4.8 mm, p < 0.05) and LV longitudinal strain (−18.8 ± 3.2% vs. −22.9 ± 3.3%, p < 0.05) decreased. Compared with recent migrants, longer-term migrants had recovered RV structure and functions with slightly improved RV and LV longitudinal strain, though still lower than lowlander controls; LV size remained small with increased mass index (68.3 ± 12.7 vs. 59.3 ± 9.6, p < 0.05). In contrast, native Tibetans had slightly increased PASP (26.1 ± 3.4 mmHg vs. 21.1 ± 4.2 mmHg, p < 0.05) with minimally altered cardiac deformation compared to lowlanders.ConclusionRight ventricular systolic function is impaired in recent (5 years) but without impairment of LV systolic or diastolic function. In contrast, cardiac size, structure, and function of native Tibetans are more similar to those of lowland dwelling Hans.

The design, implementation, and outcome of game-based learning for learners with disabilities have not been sufficiently examined systematically. Particularly, learner-based and contextual factors, as well as the essential roles played by various stakeholders, have not been addressed when game-based learning applications are used in special education. Therefore, a systematic literature review using the Activity Theory (AT) was conducted to analyse studies about game-based learning for learners with disabilities. Content analysis of 96 studies reported relevant information with respect to each activity component—(a) subject (learners with disabilities), (b) technology (game-based learning applications), (c) object (target skills or behaviours), (d) rules (implementation procedure and performance measures), (e) community (learners with disabilities, special education professionals, and parents), (f) division of labour (among learners, professionals, and parents) and (g) outcome (performance of target skills or behaviours). Furthermore, this study identified existing gaps from the reviewed studies, including occasional lack of parental engagement, difficulty of standardising performance measures due to the heterogeneity of learner profiles and contradictions (e.g., opposing views among experts on the role of educational games in social interactions). Finally, recommendations were made under each activity component. The study concluded that both general and domain-specific guidelines should be created for each disability category proposed in this review to assist practitioners who wish to use game-based learning with learners with disabilities.

Background: Advanced age is associated with poor outcomes in cardiovascular emergencies. We sought to determine the association of age, use of support devices and shock severity on mortality in cardiogenic shock (CS).Methods: Characteristics and outcomes in CS patients included in the Cardiogenic Shock Work Group (CSWG) registry from 8 US sites between 2016 and 2019 were retrospectively reviewed. Patients were subdivided by age into quintiles and Society for Cardiovascular Angiography & Interventions (SCAI) shock severity.Results: We reviewed 1,412 CS patients with a mean age of 59.9 ± 14.8 years, including 273 patients > 73 years of age. Older patients had significantly higher comorbidity burden including diabetes, hypertension and coronary artery disease. Veno-arterial extracorporeal membrane oxygenation was used in 332 (23%) patients, Impella in 410 (29%) and intra-aortic balloon pump in 770 (54%) patients. Overall in-hospital survival was 69%, which incrementally decreased with advancing age (p < 0.001). Higher age was associated with higher mortality across all SCAI stages (p = 0.003 for SCAI stage C; p < 0.001 for SCAI stage D; p = 0.005 for SCAI stage E), regardless of etiology (p < 0.001).Conclusion: Increasing age is associated with higher in-hospital mortality in CS across all stages of shock severity. Hence, in addition to other comorbidities, increasing age should be prioritized during patient selection for device support in CS.

Despite the wide recognition that strongly interacting species can influence distributions of other species, species interactions are often disregarded when assessing or projecting biodiversity distributions. In particular, it remains largely uncharted the extent to which the disappearance of a keystone species cast repercussions in the species composition of future communities. We tested whether an avian top predator can exert both positive and negative effects on spatial distribution of other species, and if these effects persist even after the predator disappeared. We acquired bird count data at different distances from occupied and non-occupied nests of Northern goshawks Accipiter gentilis. Using a Bayesian joint species distribution model, we found that large bird species (preferred prey) are less abundant in the proximity of nests occupied by goshawks, whereas smaller species –expected to get protection from subordinate predators displaced by goshawks– more often showed an opposite association. These spatial differences level off gradually, but still persist for years after the goshawks have disappeared. This indicates that the composition of local bird populations and communities might be conditional on past species interactions. Therefore, endeavors centered around species distributions could largely benefit from acknowledging the local extinction of keystone species.

White leaf spot can cause significant damage to many economically important Brassicaceae crops, including oilseed rape, vegetable, condiment, and fodder Brassica species, and recently has been identified as a re-emerging disease. The causal agent, Neopseudocercosporella capsellae, produces foliar, stem, and pod lesions under favorable weather conditions. N. capsellae secretes cercosporin, a non-host specific, photo-activated toxin, into the host tissue during the early infection process. The pathogen has an active parasitic stage on the living host and a sexual or asexual saprobic stage on the dead host. Where the sexual stage exists, ascospores initiate the new disease cycle, while in the absence of the sexual stage, conidia produced by the asexual stage initiate new disease cycles. Distribution of the pathogen is worldwide; however, epidemiology and disease severity differ between countries or continents, with it being more destructive in Subtropical, Mediterranean, or Temperate climate regions with cool and wet climates. The pathogen has a wide host range within Brassicaceae. Brassica germplasm show varied responses from highly susceptible to completely resistant to pathogen invasion and significant susceptibility differences are observed among major crop species. Cultural practices only provide effective disease control when the climate is not conducive. An increase in the susceptible host population and favorable weather conditions have together favored the recent rise in white leaf spot disease occurrence and spread. The lack of understanding of variation in pathogen virulence and associated resistant gene sources within brassicas critically limits the potential to develop efficient control measures.

Background: Right ventricular failure (RVF) is associated with increased mortality among patients receiving left ventricular mechanical circulatory support (LV-MCS) for cardiogenic shock and requires prompt recognition and management. Increased central venous pressure (CVP) is an indicator of potential RVF.Objectives: We studied whether elevated CVP during LV-MCS for acute myocardial infarction complicated by cardiogenic shock is associated with higher mortality.Methods: Between January 2014 and June 2019, we analyzed hemodynamic parameters during Impella LV-MCS from 28 centers in the United States participating in the global, prospective catheter-based ventricular assist device (cVAD) study. A total of 132 patients with a documented CVP measurement while on Impella left-sided support for cardiogenic shock were identified.Results: CVP was significantly higher among patients who died in the hospital (14.0 vs. 11.7 mmHg, p = 0.014), and a CVP >12 identified patients at significantly higher risk for in-hospital mortality (65 vs. 45%, p = 0.02). CVP remained significantly associated with in-hospital mortality even after adjustment in a multivariable model (adjusted OR 1.10 [95% CI 1.02–1.19] per 1 mmHg increase). LV-MCS suction events were non-significantly more frequent among patients with high vs. low CVP (62.11 vs. 7.14 events, p = 0.067).Conclusion: CVP is a single, readily accessible hemodynamic parameter which predicts a higher rate of short-term mortality and may identify subclinical RVF in patients receiving LV-MCS for cardiogenic shock.

Background: In-hospital mortality in acute myocardial infarction-related cardiogenic shock (AMI-CS) remains high. The only adequately powered randomized trial showed no benefit of routine use of the intra-aortic balloon pump in AMI-CS. We compared individually predicted mortality using CardShock- and IABP-Shock II-scores in AMI-CS patients treated with an Impella microaxial pump, who met the IABP-Shock II-trials inclusion/exclusion criteria, to observed mortality on circulatory support in order to determine whether standardized use of an Impella microaxial flow-pump in AMI-CS is associated with lower than predicted mortality rates and whether timing of implantation or selecting patients based on predicted risk is meaningful.Methods and Results: We analyzed data from 166 consecutive Impella-treated AMI-CS patients meeting the inclusion/exclusion criteria of the IABP-Shock II-trial (age 64 ± 11 years). Thirty-nine percentage of 64 patients had been resuscitated before Impella implantation. Overall 30-day mortality was 42%. Mortality was higher in resuscitated patients (50 vs. 36%, p = 0.0452) and when Impella was implanted post-PCI (Impella-pre-PCI: 28%, Impella-post-PCI: 51%, p = 0.0039). While in both score systems there was no significant difference between predicted and observed overall 30-day mortality, predicted mortality was significantly higher than observed mortality on Impella support only for individuals with highest predicted risk based on CardShock score (predicted 77 vs. observed 51%, p = 0.025).Conclusions: Our retrospective analysis suggests that the use of the Impella microaxial pump may be effective in selected cases of high risk patients with AMI-CS.Condensed abstract: Mortality is high in acute myocardial infarction-related cardiogenic shock despite rapid revascularization. Haemodynamic support with an intraortic balloon pump does not reduce mortality. In this retrospective registry including 166 consecutive IABP-Shock II-eligible cardiogenic shock patients in four dedicated shock centers, observed mortality on circulatory support with an Impella was significantly lower than predicted in patients with highest mortality risk. Implantation prior to PCI in acute myocardial infarction-related cardiogenic shock seemed to be associated with lower mortality than implantation post PCI.

IntroductionBipolar disorder (BD) is characterized by recurrent episodes of depression and mania and affects up to 2% of the population worldwide. Patients suffering from bipolar disorder have a reduced life expectancy of up to 10 years. The increased mortality might be due to a higher rate of somatic diseases, especially cardiovascular diseases. There is however also evidence for an increased rate of diabetes mellitus in BD, but the reported prevalence rates vary by large.Material and Methods85 bipolar disorder patients were recruited in the framework of the BiDi study (Prevalence and clinical features of patients with Bipolar Disorder at High Risk for Type 2 Diabetes (T2D), at prediabetic state and with manifest T2D) in Dresden and Würzburg. T2D and prediabetes were diagnosed measuring HBA1c and an oral glucose tolerance test (oGTT), which at present is the gold standard in diagnosing T2D. The BD sample was compared to an age-, sex- and BMI-matched control population (n = 850) from the Study of Health in Pomerania cohort (SHIP Trend Cohort).ResultsPatients suffering from BD had a T2D prevalence of 7%, which was not significantly different from the control group (6%). Fasting glucose and impaired glucose tolerance were, contrary to our hypothesis, more often pathological in controls than in BD patients. Nondiabetic and diabetic bipolar patients significantly differed in age, BMI, number of depressive episodes, and disease duration.DiscussionWhen controlled for BMI, in our study there was no significantly increased rate of T2D in BD. We thus suggest that overweight and obesity might be mediating the association between BD and diabetes. Underlying causes could be shared risk genes, medication effects, and lifestyle factors associated with depressive episodes. As the latter two can be modified, attention should be paid to weight changes in BD by monitoring and taking adequate measures to prevent the alarming loss of life years in BD patients.

Predictive computation models offer the potential to uncover the mechanisms of treatments whose actions cannot be easily determined by experimental or imaging techniques. This is particularly relevant for investigating left ventricular mechanical assistance, a therapy for end-stage heart failure, which is increasingly used as more than just a bridge-to-transplant therapy. The high incidence of right ventricular failure following left ventricular assistance reflects an undesired consequence of treatment, which has been hypothesized to be related to the mechanical interdependence between the two ventricles. To investigate the implication of this interdependence specifically in the setting of left ventricular assistance device (LVAD) support, we introduce a patient-specific finite-element model of dilated chronic heart failure. The model geometry and material parameters were calibrated using patient-specific clinical data, producing a mechanical surrogate of the failing in vivo heart that models its dynamic strain and stress throughout the cardiac cycle. The model of the heart was coupled to lumped-parameter circulatory systems to simulate realistic ventricular loading conditions. Finally, the impact of ventricular assistance was investigated by incorporating a pump with pressure-flow characteristics of an LVAD (HeartMate II™ operating between 8 and 12 k RPM) in parallel to the left ventricle. This allowed us to investigate the mechanical impact of acute left ventricular assistance at multiple operating-speeds on right ventricular mechanics and septal wall motion. Our findings show that left ventricular assistance reduces myofiber stress in the left ventricle and, to a lesser extent, right ventricle free wall, while increasing leftward septal-shift with increased operating-speeds. These effects were achieved with secondary, potentially negative effects on the interventricular septum which showed that support from LVADs, introduces unnatural bending of the septum and with it, increased localized stress regions. Left ventricular assistance unloads the left ventricle significantly and shifts the right ventricular pressure-volume-loop toward larger volumes and higher pressures; a consequence of left-to-right ventricular interactions and a leftward septal shift. The methods and results described in the present study are a meaningful advancement of computational efforts to investigate heart-failure therapies in silico and illustrate the potential of computational models to aid understanding of complex mechanical and hemodynamic effects of new therapies.

PURPOSE: Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. METHODS: Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. RESULTS: The newly characterized ligands possess an up to six-fold higher potency (EC50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. CONCLUSION: The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.