Search

The aim of the present study was to monitor the dynamics and to measure the safety and efficacy of a live, attenuated, thermosensitive Mycoplasma anserisalpingitidis vaccine candidate, namely MA271, in geese breeder flocks under field conditions. Two rearing flocks were vaccinated with MA271 at 4 weeks of age and boosted at 24 weeks of age by cloaca inoculation (1 ml) and eye-dropping (60 µl). The geese then were transported to multi-aged breeding farms. Two breeding flocks served as controls. Colonization of the cloaca by MA271 showed 75% maximum prevalence between 4 and 6 weeks after the first vaccination. Then the prevalence decreased to 25% until the cooler, humid fall months which coincided with the booster vaccination. Boosting raised cloacal colonization to 100%. No clinical signs were observed in the vaccinated birds. After transportation to five multi-aged breeding farms, the wild-type strain appeared as well as MA271 in three flocks. In one flock, the wild-type strain completely displaced MA271, while in one flock only MA271 was detected. Only wild-type strains were detected in the control flocks; however, due to an HPAI outbreak, both flocks were exterminated before the end of the study. Based on the available data, the median percentage of infertile eggs was 3.7-5.1% in the MA271 vaccinated flocks, and 7.7% in the non-vaccinated flock. In conclusion, MA271 can colonize the cloaca of geese under field conditions. MA271 proved to be safe and presumably protects against M. anserisalpingitidis- induced reproduction losses.

Purpose: We aimed to identify the optimal reconstruction settings based on qualitative and quantitative image quality parameters on standard and ultra-high resolution (UHR) images using photon-counting CT (PCCT)., Method: We analysed 45 patients, 29 with standard and 16 with UHR acquisition, applying both smoother and sharper kernel settings. Coronary CT angiography images were performed on a dual-source PCCT system using standard (0.4/0.6 mm slice thickness, Bv40/Bv44 kernels, QIR levels 0-4) or UHR acquisition (0.2/0.4 mm slice thickness, Bv44/Bv56 kernels, QIR levels 0-4). Qualitative image quality was assessed using a 4-point Likert scale. Image noise (SD), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated in both the proximal and distal segments., Results: On standard resolution, larger slice thickness resulted in an average increase of 12.5 % in CNR, whereas sharper kernel led to an average 8.7 % decrease in CNR. Highest CNR was measured on 0.6 mm, Bv40, QIR4 images and lowest on 0.4 mm, Bv44, QIR0 images: 25.8 ± 4.1vs.8.3 ± 1.6 (p < 0.001). On UHR images, highest CNR was observed on 0.4 mm, Bv40, QIR4 and lowest on 0.2 mm, Bv56 and QIR0 images: 21.5 ± 3.9vs.3.6 ± 0.8 (p < 0.001). Highest qualitative image quality was found on images with Bv44 kernel and QIR level 3/4 with both slice thicknesses on standard reconstruction. Additionally, Bv56 with QIR4 on 0.2 mm slice thickness images showed highest subjective image quality. Preserved distal vessel visualization was detected using QIR 2-4, Bv56 and 0.2 mm slice thickness., Conclusions: Photon-counting CT demonstrated high qualitative and quantitative image quality for the assessment of coronaries and stents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Institutional betrayal (IB) is well-documented among survivors of gender-based violence seeking help and/or reporting incidents of violence in various settings, including college campuses and health care settings. Two of the most common institutions from which survivors seek help are the criminal and civil legal systems; however, less is known about the experiences of IB among survivors interfacing with those systems. Previous studies exploring IB have implemented the Institutional Betrayal Questionnaire (IBQ) and its various adaptations, but this scale has not yet been analyzed in the criminal or civil legal context, nor has it been analyzed among racially marginalized survivors. This paper explores the potential for utilizing the IBQ-Health among a sample of 199 Black and Hispanic survivors of intimate partner violence (IPV) who sought help from the criminal and/or civil legal system(s). An exploratory factor analysis was conducted to explore the fit of the measure to the data. Results suggest that the measure as it has previously been used does not demonstrate strong reliability or fit with this population or institution. Possible explanations and future directions are explored, including support for developing and piloting a new measure to assess IB among Black and Hispanic survivors of interpersonal violence who are seeking help from criminal and civil legal institutions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Evidence suggests that depressive symptomatology is a consequence of network dysfunction rather than lesion pathology. We studied whole-brain functional connectivity using a Minimum Spanning Tree as a graph-theoretical approach. Furthermore, we examined functional connectivity in the Default Mode Network, the Frontolimbic Network (FLN), the Salience Network, and the Cognitive Control Network. All 183 elderly subjects underwent a comprehensive neuropsychological evaluation and a 3 Tesla brain MRI scan. To assess the potential presence of depressive symptoms, the 13-item version of the Beck Depression Inventory (BDI) or the Geriatric Depression Scale (GDS) was utilized. Participants were assigned into three groups based on their cognitive status: amnestic mild cognitive impairment (MCI), non-amnestic MCI, and healthy controls. Regarding affective symptoms, subjects were categorized into depressed and non-depressed groups. An increased mean eccentricity and network diameter were found in patients with depressive symptoms relative to non-depressed ones, and both measures showed correlations with depressive symptom severity. In patients with depressive symptoms, a functional hypoconnectivity was detected between the Anterior Cingulate Cortex (ACC) and the right amygdala in the FLN, which impairment correlated with depressive symptom severity. While no structural difference was found in subjects with depressive symptoms, the volume of the hippocampus and the thickness of the precuneus and the entorhinal cortex were decreased in subjects with MCI, especially in amnestic MCI. The increase in eccentricity and diameter indicates a more path-like functional network configuration that may lead to an impaired functional integration in depression, a possible cause of depressive symptomatology in the elderly., (© 2024. The Author(s).)

Objectives: Visualizing left atrial anatomy including the pulmonary veins (PVs) is important for planning the procedure of pulmonary vein isolation with ablation in patients with atrial fibrillation (AF). The aims of our study are to investigate the feasibility of the 3D whole-heart bright-blood and black-blood phase-sensitive (BOOST) inversion recovery sequence in patients with AF scheduled for ablation or electro-cardioversion, and to analyze the correlation between image quality and heart rate and rhythm of patients., Methods: BOOST was performed for assessing PVs both with T2 preparation pre-pulse (T2prep) and magnetization transfer preparation (MTC) in 45 patients with paroxysmal or permanent AF scheduled for ablation or electro-cardioversion. Image quality analyses were performed by two independent observers. Qualitative assessment was made using the Likert scale; for quantitative analysis, signal to noise ratios (SNR) and contrast to noise ratios (CNR) were calculated for each PV. Heart rate and rhythm were analyzed based on standard 12-lead ECGs., Results: All MTC-BOOST acquisitions achieved diagnostic quality in the PVs, while a significant proportion of T2prep-BOOST images were not suitable for assessing PVs. SNR and CNR values of the MTC-BOOST bright-blood images were higher if patients had sinus rhythm. We found a significant or nearly significant negative correlation between heart rate and the SNR and CNR values of MTC-BOOST bright-blood images., Conclusion: 3D whole-heart MTC-BOOST bright-blood imaging is suitable for visualizing the PVs in patients with AF, producing diagnostic image quality in 100% of cases. However, image quality was influenced by heart rate and rhythm., Clinical Relevance Statement: The novel 3D whole-heart BOOST CMR sequence needs no contrast administration and is performed during free-breathing; therefore, it is easy to use for a wide range of patients and is suitable for visualizing the PVs in patients with AF., Key Points: • The applicability of the novel 3D whole-heart bright-blood and black-blood phase-sensitive sequence to pulmonary vein imaging in clinical practice is unknown. • Magnetization transfer-bright-blood and black-blood phase-sensitive imaging is suitable for visualizing the pulmonary veins in patients with atrial fibrillation with excellent or good image quality. • Bright-blood and black-blood phase-sensitive cardiac magnetic resonance sequence is easy to use for a wide range of patients as it needs no contrast administration and is performed during free-breathing., (© 2023. The Author(s).)

Mild cognitive impairment (MCI) is a potential therapeutic window in the prevention of dementia; however, automated detection of early cognitive deterioration is an unresolved issue. The aim of our study was to compare various classification approaches to differentiate MCI patients from healthy controls, based on rs-fMRI data, using machine learning (ML) algorithms. Own dataset (from two centers) and ADNI database were used during the analysis. Three fMRI parameters were applied in five feature selection algorithms: local correlation, intrinsic connectivity, and fractional amplitude of low frequency fluctuations. Support vector machine (SVM) and random forest (RF) methods were applied for classification. We achieved a relatively wide range of 78-87% accuracy for the various feature selection methods with SVM combining the three rs-fMRI parameters. In the ADNI datasets case we can also see even 90% accuracy scores. RF provided a more harmonized result among the feature selection algorithms in both datasets with 80-84% accuracy for our local and 74-82% for the ADNI database. Despite some lower performance metrics of some algorithms, most of the results were positive and could be seen in two unrelated datasets which increase the validity of our methods. Our results highlight the potential of ML-based fMRI applications for automated diagnostic techniques to recognize MCI patients., (© 2023. The Author(s).)

We demonstrated the operation of a 46.9-nm capillary discharge Ar  + 8 -laser excited by electrical pulses at a very low voltage (35 - 45 kV), which is approximately two times lower than previously reported. The decrease in pulse voltage not only allows for further reduction in the size of the laser's excitation part, but also a principal shift to the experimental methods, techniques, and technologies used in ordinary pulsed gas lasers operating in the ultraviolet, visible, and infrared regions of the spectra. In an argon-filled alumina capillary with an inner diameter of 3.1 mm and a length of 22 cm, laser pulses with an energy of 4 µJ and a duration of 1.6 ns were generated. The laser produces a beam with a Gaussian intensity distribution and an FWHM divergence of 1.9 mrad. The results could be particularly useful in the development of compact, practical soft x-ray capillary lasers for use in small laboratories at educational and research institutions.

Introduction: Obtaining accurate coronary artery calcium (CAC) score measurements from CCTA datasets with virtual non-iodine (VNI) algorithms would reduce acquisition time and radiation dose. We aimed to assess the agreement of VNI-derived and conventional true non-contrast (TNC)-based CAC scores and to identify the predictors of accuracy., Methods: CCTA datasets were acquired with either 120 or 140 ​kVp. CAC scores and volumes were calculated from TNC and VNI images in 197 consecutive patients undergoing CCTA. CAC density score, mean volume/lesion, aortic Hounsfield units and standard deviations were then measured. Finally, percentage deviation (VNI - TNC/TNC∗100) of CTA-derived CAC scores from non-enhanced scans was calculated for each patient. Predictors (including anthropometric and acquisition parameters, as well as CAC characteristics) of the degree of discrepancy were evaluated using linear regression analysis., Results: While the agreement between TNC and VNI was substantial (mean bias, 6.6; limits of agreement, 178.5/145.3), a non-negligible proportion of patients (36/197, 18.3%) were falsely reclassified as CAC score ​= ​0 on VNI. The use of higher tube voltage significantly decreased the percentage deviation relative to TNC-based values (β ​= ​-0.21 [95%CI: 0.38 to -0.03], p ​= ​0.020) and a higher CAC density score also proved to be an independent predictor of a smaller difference (β ​= ​-0.22 [95%CI: 0.37 to -0.07], p ​= ​0.006)., Conclusion: The performance of VNI-based calcium scoring may be improved by increased tube voltage protocols, while the accuracy may be compromised for calcified lesions of lower density. The implementation of VNI in clinical routine, however, needs to be preceded by a solution for detecting smaller lesions as well., Competing Interests: Declaration of conflicting interest M. V–N.: None; A. V–S. received research grant from Siemens and consulting fees from Bayer and Elucid Bioimaging.; T. E. received travel support and speaker fee from Siemens Healthineers and institutional research support from Siemens Healthineers; E. Zs.: None; N. F.: None; B. Sch. is an employee of Siemens Healthineers, Forchheim, Germany; T. N. is an employee of Siemens Healthineers, Forchheim, Germany; M. K.: is an employee of Siemens Healthineers, Forchheim, Germany; B.V.: None; M.B.: None; M.K.: None; A.K.: None; B.M.: None; P. M-H.: None; B. Sz.: None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

Introduction: Structural and functional heart abnormalities can be examined non-invasively with cardiac magnetic resonance imaging (CMR). Thanks to the development of MR devices, diagnostic scans can capture more and more relevant information about possible heart diseases. T1 and T2 mapping are such novel technology, providing tissue specific information even without the administration of contrast material. Artificial intelligence solutions based on deep learning have demonstrated state-of-the-art results in many application areas, including medical imaging. More specifically, automated tools applied at cine sequences have revolutionized volumetric CMR reporting in the past five years. Applying deep learning models to T1 and T2 mapping images can similarly improve the efficiency of post-processing pipelines and consequently facilitate diagnostic processes., Methods: In this paper, we introduce a deep learning model for myocardium segmentation trained on over 7,000 raw CMR images from 262 subjects of heterogeneous disease etiology. The data were labeled by three experts. As part of the evaluation, Dice score and Hausdorff distance among experts is calculated, and the expert consensus is compared with the model's predictions., Results: Our deep learning method achieves 86% mean Dice score, while contours provided by three experts on the same data show 90% mean Dice score. The method's accuracy is consistent across epicardial and endocardial contours, and on basal, midventricular slices, with only 5% lower results on apical slices, which are often challenging even for experts., Conclusions: We trained and evaluated a deep learning based segmentation model on 262 heterogeneous CMR cases. Applying deep neural networks to T1 and T2 mapping could similarly improve diagnostic practices. Using the fine details of T1 and T2 mapping images and high-quality labels, the objective of this research is to approach human segmentation accuracy with deep learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kalapos, Szabó, Dohy, Kiss, Merkely, Gyires-Tóth and Vágó.)

Introduction: Left atrial appendage (LAA) thrombus is the most common source of embolization in atrial fibrillation (AF). Transesophageal echocardiography (TEE) is the gold standard method for LAA thrombus exclusion. Our pilot study aimed to compare the efficacy of a new non-contrast-enhanced cardiac magnetic resonance (CMR) sequence (BOOST) with TEE for the detection of LAA thrombus and to evaluate the usefulness of BOOST images for planning radiofrequency catheter ablation (RFCA) compared with left atrial (LA) contrast-enhanced computed tomography (CT). We also attempted to assess the patients' subjective experiences with TEE and CMR., Methods: Patients with AF undergoing either electrical cardioversion or RFCA were enrolled. Participants underwent pre-procedural TEE and CMR scans to evaluate LAA thrombus status and pulmonary vein anatomy. Patient experiences with TEE and CMR were assessed using a questionnaire developed by our team. Some patients scheduled for RFCA also had pre-procedural LA contrast-enhanced CT. In such cases, the operating physician was asked to subjectively define the quality of the CT and CMR scan on a scale of 1-10 (1 = worst, 10 = best) and comment on CMR's usefulness in RFCA planning., Results: Seventy-one patients were enrolled. In 94.4%, both TEE and CMR excluded, and in 1 patient, both modalities reported the presence of LAA thrombus. In 1 patient, TEE was inconclusive, but CMR excluded LAA thrombus. In 2 patients, CMR could not exclude the presence of thrombus, but in 1 of those cases, TEE was also indecisive. During TEE, 67%, during CMR, only 1.9% of patients reported pain ( p  < 0.0001), and 89% would prefer CMR in case of a repeat examination. The quality of the left atrial contrast-enhanced CT scans was better compared with the image quality of the CMR BOOST sequence [8 (7-9) vs. 6 (5-7), p  < 0.0001]. Still, the CMR images were useful for procedural planning in 91% of cases., Conclusion: The new CMR BOOST sequence provides appropriate image quality for ablation planning. The sequence might be useful for excluding larger LAA thrombi; however, its accuracy in detecting smaller thrombi is limited. Most patients preferred CMR over TEE in this indication., Competing Interests: KK, RN, and MK are employees of Siemens Healthineers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Orbán, Dohy, Suhai, Nagy, Salló, Boga, Kiss, Kunze, Neji, Botnar, Prieto, Gellér, Merkely, Vágó and Szegedi.)

Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell hi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy., Competing Interests: Declaration of interests M.J.P. has served as consultant for AstraZeneca, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, Merck, Siamab Therapeutics, Third Rock Ventures, and Tidal. R.W. has served as a consultant for Moderna, Lumicell, Seer Biosciences, Earli, and Accure Health. The wife of R.B. is an employee and shareholder of CSL Behring, and R.B. received a speaker’s fee from Janssen., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Left common pulmonary vein is the most common anatomical variant of pulmonary veins that may affect the outcome of pulmonary vein isolation., Objective: Our aim was to compare procedural data and outcomes in patients with common trunk versus normal left atrial anatomy for radiofrequency and cryoballoon catheter ablation., Method: Data from patients who underwent pulmonary vein isolation for atrial fibrillation and had a preprocedural cardiac CT scan at our Institution between 01. 10. 2019 and 10. 03. 2022 were retrospectively evaluated. We defined a common trunk where the left superior and inferior pulmonary vein merged at least 5 mm before the left atrial ostium., Results: From the study population (n = 210), data from 42 patients with a left common trunk (LCPV group) and 60 patients with normal left atrial anatomy (control group) were examined. No significant differences were found between the common trunk and the control group in terms of demographic data. There was no significant difference between the two groups in procedural data for radiofrequency and cryoballoon ablation (procedure time, fluoroscopy time, left atrial dwelling time, radiation dose). After radiofrequency ablation, the success rate at 1-year follow-up was 72.0% in the common trunk group and 76.2% in the control group (p = 0.659). For cryoballoon ablation, the success rate was 64.7% and 69.2% for common trunk and normal anatomy, respectively (p = 0.641)., Conclusion: There was no significant difference in the procedural parameters and clinical outcome between patients with left common pulmonary vein and those with normal left atrial anatomy. Both radiofrequency and cryoballoon ablation techniques are well suited for this population. Orv Hetil. 2023; 164(4): 140-147.

Introduction: Based on a longtime voluntary registry founded by the Ministry of Healthcare of the Slovak Republic in 2012 and endorsed by the National Institute of Cardiovascular Diseases, well-defined data of all adult cardiac surgery procedures performed during the year 2021 are analyzed., Material and Method: For this period, data on 947 procedures were submitted to the registry., Results: The unadjusted in-hospital survival rate for the 352 isolated coronary artery bypass grafting procedures including urgent and emergency procedures (relationship on-/off pump 3.8 : 1) was 96.3 %. For 331 isolated heart valve procedures (33 transcatheter interventions), it was 95.5 %. Concerning ventricular assist devices, 19 implantations were registered. In 2021 the number of isolated heart transplantations was 16, which is a decrease by 38.5 % as compared to the previous year., Conclusion: These annually registered data are collected from voluntary public reporting and accumulate actual information on nearly all heart procedures carried out in the National Institute of Cardiovascular Diseases. These data capture advancements in heart medicine and represent the basis for quality management. In addition, the registry demonstrates that the provision of cardiac surgery in Slovakia is up to date, appropriate, and nationwide patient treatment is guaranteed all the time (Tab. 14, Fig. 2, Ref. 5). Text in PDF www.elis.sk Keywords: heart valve surgery, outcomes, coronary artery bypass grafting, aortic surgery, heart transplantation.

Junctional adhesion molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate myeloid cell activation. Infiltration of myeloid cells is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on tumor-infiltrating myeloid cells is little understood. Here we show that systemic cancer-associated inflammation in mice enhanced JAM-A expression selectively on circulating monocytes in an IL1β-dependent manner. Using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that loss of JAM-A did not influence the transcriptional reprogramming of myeloid cells in the tumor microenvironment. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells, and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment and reprogramming., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kiss, Lebegge, Murgaski, Van Damme, Kancheva, Brughmans, Scheyltjens, Talebi, Awad, Elkrim, Bardet, Arnouk, Goyvaerts, Swinnen, Nana, Van Ginderachter and Laoui.)

Ample evidence shows that the momentary performance can dissociate from the underlying knowledge (competence). Under what circumstances such dissociation occurs, however, remains unclear. Here we tested how temporal factors, and more specifically, the elapsed time between subsequent events affects the dissociation between performance and competence by systematically manipulating the stimulus presentation rates during and after learning. Participants completed a probabilistic sequence learning task with a fast (120 msec) or a slow (850 msec) response-to-stimulus-interval (RSI) during the Learning phase and they were tested with both RSIs 24 h later (Testing phase). We also tested whether they gained explicit knowledge about the sequence or their knowledge remained implicit. Our results revealed higher reaction time learning scores when tested with the fast RSI, irrespective of the RSI during learning, suggesting that faster presentation rates can help better express the acquired knowledge, leading to increased performance measures. For accuracy, participants showed higher learning scores when tested with the same presentation rate as the one that they encountered during learning. The acquired knowledge remained implicit in both groups, suggesting that the observed findings were not confounded by differences in awareness gained in the two groups. Overall, our study highlights that the momentary performance does not always accurately reflect the underlying knowledge, and temporal factors seem to influence this dissociation. Our findings have theoretical, methodological, and translational implications that likely extend beyond learning and memory to other functions and domains as well, including aspects of decision-making, perception, theory of mind, and language., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

Mild cognitive impairment (MCI) is the prodromal phase of dementia, and it is highly underdiagnosed in the community. We aimed to develop an automated, rapid (< 5 min), electronic screening tool for the recognition of MCI based on hand movement analysis. Sixty-eight individuals participated in our study, 46 healthy controls and 22 patients with clinically defined MCI. All participants underwent a detailed medical assessment including neuropsychology and brain MRI. Significant differences were found between controls and MCI groups in mouse movement characteristics. Patients showed higher level of entropy for both the left (F = 5.24; p = 0.001) and the right hand (F = 8.46; p < 0.001). Longer time was required in MCI to perform the fine motor task (p < 0.005). Furthermore, we also found significant correlations between mouse movement parameters and neuropsychological test scores. Correlation was the strongest between motor parameters and Clinical Dementia Rating scale (CDR) score (average r: - 0.36, all p's < 0.001). Importantly, motor parameters were not influenced by age, gender, or anxiety effect (all p's > 0.05). Our study draws attention to the utility of hand movement analysis, especially to the estimation of entropy in the early recognition of MCI. It also suggests that our system might provide a promising tool for the cognitive screening of large populations., (© 2022. The Author(s).)

A growing number of artificial intelligence (AI)-based systems are being proposed and developed in cardiology, driven by the increasing need to deal with the vast amount of clinical and imaging data with the ultimate aim of advancing patient care, diagnosis and prognostication. However, there is a critical gap between the development and clinical deployment of AI tools. A key consideration for implementing AI tools into real-life clinical practice is their "trustworthiness" by end-users. Namely, we must ensure that AI systems can be trusted and adopted by all parties involved, including clinicians and patients. Here we provide a summary of the concepts involved in developing a "trustworthy AI system." We describe the main risks of AI applications and potential mitigation techniques for the wider application of these promising techniques in the context of cardiovascular imaging. Finally, we show why trustworthy AI concepts are important governing forces of AI development., Competing Interests: Author SEP provides consultancy to Cardiovascular Imaging Inc, Calgary, Alberta, Canada. Author MK was employed by Siemens Healthcare Hungary. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Szabo, Raisi-Estabragh, Salih, McCracken, Ruiz Pujadas, Gkontra, Kiss, Maurovich-Horvath, Vago, Merkely, Lee, Lekadir and Petersen.)

Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of αCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of αCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to αCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to αCD40 suggest that different tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists., Significance: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8+ T-cell-driven responses to CD40 agonist therapy in cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)

With the increase in health awareness more and more attention is paid to how manufacturers can respond to ever-changing consumer needs. This is especially true for the market of popular consumer goods such as chocolate. In order to understand Hungarian consumers' preferences in chocolate bars, we used the stated choice experiment method in our research. The attributes of our experiment included brand (manufacturer and private label), type (milk, dark, and white), a health claim (sugar free), as well as price, and our model estimations were done using the multinomial logit specification. In order to increase the explained rate of utility perceived by respondents, we also estimated a hybrid model containing a latent variable (representing consumers' brand loyalty). Our results reveal that the respondents showed a clear preference for manufacturer brands compared to private label brands. Regarding the type of chocolate, we found that milk chocolate received the most positive evaluation, which was followed by dark and white chocolate, respectively; we also demonstrated that sugar free products have a negative rating. In line with our preliminary expectations, a rise in the price of the product has a negative impact on utility as perceived by consumers. Brand loyalty is most characteristic of young and highly educated respondents, and a rise in brand loyalty lead to an increase in the preference towards manufacturer brand products compared to private label brand products., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption. Furthermore, differences between intestinal drug transport processes of children and adults were explored as well as the possible impact of age. Fresh terminal ileal leftover tissues from both children and adults were collected during surgery and prepared for Ussing chamber experiments. Paracellular (enalaprilat), transcellular (propranolol), and carrier-mediated drug transport by MDR1 (talinolol) and BCRP (rosuvastatin) were determined with the Ussing chamber methodology. We calculated apparent permeability coefficients and efflux ratios and explored their relationship with postnatal age. The success rate for the Ussing chamber experiments, as determined by electrophysiological measurements, was similar between children (58%, N = 15, median age: 44 weeks; range 8 weeks to 17 years) and adults (67%, N = 13). Mean serosal to mucosal transport of talinolol by MDR1 and rosuvastatin by BCRP was higher in adult than in pediatric tissues (p = 0.0005 and p = 0.0091). In contrast, within our pediatric cohort, there was no clear correlation for efflux transport across different ages. In conclusion, the Ussing chamber is a suitable model to explore pediatric intestinal drug absorption and can be used to further elucidate ontogeny of individual intestinal pharmacokinetic processes like drug metabolism and transport., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Cognitive neuroscience has highlighted the cerebral cortex while often overlooking subcortical structures. This cortical proclivity is found in basic and translational research on many aspects of cognition, especially higher cognitive domains such as language, reading, music, and math. We suggest that, for both anatomical and evolutionary reasons, multiple subcortical structures play substantial roles across higher and lower cognition. We present a comprehensive review of existing evidence, which indeed reveals extensive subcortical contributions in multiple cognitive domains. We argue that the findings are overall both real and important. Next, we advance a theoretical framework to capture the nature of (sub)cortical contributions to cognition. Finally, we propose how new subcortical cognitive roles can be identified by leveraging anatomical and evolutionary principles, and we describe specific methods that can be used to reveal subcortical cognition. Altogether, this review aims to advance cognitive neuroscience by highlighting subcortical cognition and facilitating its future investigation.

Internal models capture the regularities of the environment and are central to understanding how humans adapt to environmental statistics. In general, the correct internal model is unknown to observers, instead they rely on an approximate model that is continually adapted throughout learning. However, experimenters assume an ideal observer model, which captures stimulus structure but ignores the diverging hypotheses that humans form during learning. We combine non-parametric Bayesian methods and probabilistic programming to infer rich and dynamic individualised internal models from response times. We demonstrate that the approach is capable of characterizing the discrepancy between the internal model maintained by individuals and the ideal observer model and to track the evolution of the contribution of the ideal observer model to the internal model throughout training. In particular, in an implicit visuomotor sequence learning task the identified discrepancy revealed an inductive bias that was consistent across individuals but varied in strength and persistence., Competing Interests: The authors have declared that no competing interests exist.

Amnestic-type mild cognitive impairment (a-MCI) represents the prodromal phase of Alzheimer's disease associated with a high conversion rate to dementia and serves as a potential golden period for interventions. In our study, we analyzed the role of visuospatial (VS) functions and networks in the recognition of a-MCI. We examined 78 participants (32 patients and 46 controls) in a double-center arrangement using neuropsychology, structural, and resting-state functional MRI. We found that imaging of the lateral temporal areas showed strong discriminating power since in patients only the temporal pole ( F = 5.26, p = 0.034) and superior temporal gyrus ( F = 8.04, p < 0.001) showed reduced cortical thickness. We demonstrated significant differences between controls and patients in various neuropsychological results; however, analysis of cognitive subdomains revealed that the largest difference was presented in VS skills ( F = 8.32, p < 0.001). Functional connectivity analysis of VS network showed that patients had weaker connectivity between the left and right frontotemporal areas, while stronger local connectivity was presented between the left frontotemporal structures (FWE corrected p < 0.05). Our results highlight the remarkable potential of examining the VS system in the early detection of cognitive decline. Since resting-state setting of functional MRI simplifies the possible automatization of data analysis, detection of VS system alterations might provide a non-invasive biomarker of a-MCI., Competing Interests: MK was employed by Siemens Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Berente, Zsuffa, Werber, Kiss, Drotos, Kamondi, Csukly and Horvath.)

We examined whether endurance performance and neuromuscular fatigue would be affected by caffeine ingestion during closed- and open-loop exercises. Nine cyclists performed a closed-loop (4,000-m cycling time trial) and an open-loop exercise (work rate fixed at mean power of the closed-loop trial) 60 min after ingesting caffeine (CAF, 5 mg/kg) or placebo (PLA, cellulose). Central and peripheral fatigue was quantified via pre- to post-exercise decrease in quadriceps voluntary activation and potentiated twitch force, respectively. Test sensitivity for detecting caffeine-induced improvements in exercise performance was calculated as the mean change in time divided by the error of measurement. Caffeine ingestion reduced the time of the closed-loop trial (PLA: 375.1±14.5 s vs CAF: 368.2±14.9 s, P=0.024) and increased exercise tolerance during the open-loop trial (PLA: 418.2±99.5 s vs CAF: 552.5±106.5 s, P=0.001), with similar calculated sensitivity indices (1.5, 90%CI: 0.7-2.9 vs 2.8, 90%CI: 1.9-5.1). The reduction in voluntary activation was more pronounced (P=0.019) in open- (-6.8±8.3%) than in closed-loop exercises (-1.9±4.4%), but there was no difference between open- and closed-loop exercises for the potentiated twitch force reduction (-25.6±12.8 vs -26.6±12.0%, P>0.05). Caffeine had no effect on central and peripheral fatigue development in either mode of exercise. In conclusion, caffeine improved endurance performance in both modes of exercise without influence on post-exercise central and peripheral fatigue, with the open-loop exercise imposing a greater challenge to central fatigue tolerance.

Inhibition of the human O -linked β- N -acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N -acetyl-3,4,6-tri- O -acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO 2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O -acetyl protecting groups by NH 3 /MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone ( 5f , K i = 27 nM). This compound had a K i of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.

Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs])., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Patsalos et al.)

Most drugs are administered to children orally. An information gap remains on the protein abundance of small intestinal drug-metabolizing enzymes (DMEs) and drug transporters (DTs) across the pediatric age range, which hinders precision dosing in children. To explore age-related differences in DMEs and DTs, surgical leftover intestinal tissues from pediatric and adult jejunum and ileum were collected and analyzed by targeted quantitative proteomics for apical sodium-bile acid transporter, breast cancer resistance protein (BCRP), monocarboxylate transporter 1 (MCT1), multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein (MRP) 2, MRP3, organic anion-transporting polypeptide 2B1, organic cation transporter 1, peptide transporter 1 (PEPT1), CYP2C19, CYP3A4, CYP3A5, UDP glucuronosyltransferase (UGT) 1A1, UGT1A10, and UGT2B7. Samples from 58 children (48 ileums, 10 jejunums, age range: 8 weeks to 17 years) and 16 adults (8 ileums, 8 jejunums) were analyzed. When comparing age groups, BCRP, MDR1, PEPT1, and UGT1A1 abundance was significantly higher in adult ileum as compared with the pediatric ileum. Jejunal BCRP, MRP2, UGT1A1, and CYP3A4 abundance was higher in the adults compared with children 0-2 years of age. Examining the data on a continuous age scale showed that PEPT1 and UGT1A1 abundance was significantly higher, whereas MCT1 and UGT2B7 abundance was lower in adult ileum as compared with the pediatric ileum. Our data contribute to the deeper understanding of the ontogeny of small intestinal drug-metabolizing enzymes and drug transporters and shows DME-, DT-, and intestinal location-specific, age-related changes. SIGNIFICANCE STATEMENT: This is the first study that describes the ontogeny of small intestinal DTs and DMEs in human using liquid chromatography with tandem mass spectrometry-based targeted quantitative proteomics. The current analysis provides a detailed picture about the maturation of DT and DME abundances in the human jejunum and ileum. The presented results supply age-related DT and DME abundance data for building more accurate PBPK models that serve to support safer and more efficient drug dosing regimens for the pediatric population., (Copyright © 2021 by The Author(s).)

O-GlcNAcylation is a dynamic post-translational modification mediated by O-linked β-N-acetylglucosamine transferase (OGT) and O-GlcNAc hydrolase (OGA), that adds or removes a single β-N-acetylglucosamine (GlcNAc) moiety to or from serine/threonine residues of nucleocytosolic and mitochondrial proteins, respectively. The perturbed homeostasis of O-GlcNAc cycling results in several pathological conditions. Human OGA is a promising therapeutic target in diseases where aberrantly low levels of O-GlcNAc are experienced, such as tauopathy in Alzheimer's disease. A new class of potent OGA inhibitors, 2-acetamido-2-deoxy-d-glucono-1,5-lactone (thio)semicarbazones, have been identified. Eight inhibitors were designed and synthesized in five steps starting from d-glucosamine and with 15-55% overall yields. A heterologous OGA expression protocol with strain selection and isolation has been optimized that resulted in stable, active and full length human OGA (hOGA) isomorph. Thermal denaturation kinetics of hOGA revealed environmental factors affecting hOGA stability. From kinetics experiments, the synthesized compounds proved to be efficient competitive inhibitors of hOGA with K i -s in the range of ∼30-250 nM and moderate selectivity with respect to lysosomal β-hexosaminidases. In silico studies consisting of Prime protein-ligand refinements, QM/MM optimizations and QM/MM-PBSA binding free energy calculations revealed the factors governing the observed potencies, and led to design of the most potent analogue 2-acetamido-2-deoxy-d-glucono-1,5-lactone 4-(2-naphthyl)-semicarbazone 6g (K i  = 36 nM). The protocol employed has applications in future structure based inhibitor design targeting OGA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Food neophobia is the fear or loathing of novel food, which may result in the rejection of the unfamiliar food item. The most frequently used and most reliable tool to measure adult food neophobia is the Food Neophobia Scale (FNS), which has been translated into several languages, making it possible to compare food neophobia levels around the world. The main objective of this research has been the adaptation and validation of the FNS in Hungary. In order to achieve the research objectives, a questionnaire survey was conducted on a representative sample of 500 adults; and, primarily, multivariate statistical tools were used. We found that despite the Hungarian population's strong neophobic tendency, neophobia and neophilia are present at the same time. We identified two distinctive factors in the course of the exploratory factor analysis ("Willingness and trust" and "Rejection and particularity"), which distinctly separate the negatively and positively worded (reversed) FNS items. Based on these factors, four clusters were identified. Those belonging in the group of adventurous open-minded individuals constitute an ideal target group for the manufacturers of novel food items as well as products with unusual flavors, especially if those products also have health-enhancing and eco-friendly qualities.

The latest development in the anterior lumbar interbody fusion (ALIF) procedure is its application in the lateral position to allow for simultaneous posterior percutaneous screw placement. The technical details of the lateral ALIF technique have not yet been described. To describe the surgical anatomy relevant to the lateral ALIF approach we performed a comprehensive anatomical study. In addition, the preoperative imaging, patient positioning, planning of the skin incision, positioning of the C-arm, surgical approach, and surgical technique are discussed in detail. The technique described led to the successful use of the lateral ALIF technique in our clinical cases. No lateral ALIF procedure needed to be aborted during these cases. Our present work gives detailed anatomical background and technical details for the lateral ALIF approach. This teaching article can provide readers with sufficient technical and anatomical knowledge to assist them in performing their first lateral ALIF procedure., (© 2021 American Association of Clinical Anatomists.)

Knowing when the brain learns is crucial for both the comprehension of memory formation and consolidation and for developing new training and neurorehabilitation strategies in healthy and patient populations. Recently, a rapid form of offline learning developing during short rest periods has been shown to account for most of procedural learning, leading to the hypothesis that the brain mainly learns during rest between practice periods. Nonetheless, procedural learning has several subcomponents not disentangled in previous studies investigating learning dynamics, such as acquiring the statistical regularities of the task, or else the high-order rules that regulate its organization. Here we analyzed 506 behavioral sessions of implicit visuomotor deterministic and probabilistic sequence learning tasks, allowing the distinction between general skill learning, statistical learning, and high-order rule learning. Our results show that the temporal dynamics of apparently simultaneous learning processes differ. While high-order rule learning is acquired offline, statistical learning is evidenced online. These findings open new avenues on the short-scale temporal dynamics of learning and memory consolidation and reveal a fundamental distinction between statistical and high-order rule learning, the former benefiting from online evidence accumulation and the latter requiring short rest periods for rapid consolidation.

The Coronavirus disease 2019 (COVID-19) posed unexpected global economic and societal challenges. These include a heavy impact on mental health due to fast changing lockdown and quarantine measures, uncertainty about health and safety and the prospect of new waves of infections. To provide crisis mental health support during the pandemic, Eötvös Loránd University in Hungary launched a specialist online counselling programme, consisting of one to three sessions. The programme was available to all university members between 4th March and 25th May 2020. Overall, 47 clients received support. In this paper we discuss challenges reported by clients, key features of providing a brief mental health intervention online, reflect on counsellor experiences and give recommendations on how mental health services could be developed in the time of crisis. Most clients had challenges with developing a daily routine under quarantine; and many had hardship related to finances, housing, and distance learning. Common mental health consequences included fear from the virus and stress, anxiety, and fatigue due to the interruption to everyday life. In some cases, more complex conditions were triggered by the pandemic. Examples include addictive behaviours and symptoms of depression or psychosis. However, referring cases beyond the competency of counselling proved to be a challenge due to the closure of specialist services. Counsellors observed three key features to the online delivery of a brief crisis mental health intervention: [1] an explicit problem-oriented approach to counselling; [2] challenges of building rapport online; and [3] frames of online counselling. Counsellor experiences often overlapped with those of clients and included challenges of working from home and adjusting to online counselling methods. The possibility of online counselling allowed that mental health care could take place at all during the pandemic. Client experiences reflect findings from previous literature. Like other mental health initiatives launched to tackle COVID-19, the intervention's effectiveness was not measured given the unexpected context and short time frame for programme development. We recommend the use of impact measurement tools to develop mental health services in crises. Meanwhile, the pandemic brought to attention the need to better understand online delivery models. Counsellors should have access to training opportunities on online counselling and managing work-life balance in a remote setting. The COVID-19 counselling programme in Eötvös Loránd University, Hungary is an example of providing online mental health counselling in the time of crisis. Clearly, more studies are needed discussing delivery models and effectiveness of mental health interventions during the pandemic. Experience and knowledge sharing across practitioners should be encouraged to improve how the field reacts to unexpected, high risk events and crises., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Szlamka, Kiss, Bernáth, Kámán, Lubani, Karner and Demetrovics.)

Background: Despite the increasing number of personalized nutrition services available on the market, nutrigenomics-based level of personalization is still the exception rather than a mainstream activity. This can be partly explained by various factors of consumer acceptance of the new technology. While consumer attitudes toward genetic tests aiming to reveal the risks of a predisposition to various illnesses have already been examined by several research studies worldwide; consumer acceptance of nutrigenomics-based personalized nutrition has only been examined by a significantly lower number of papers, especially in the Central and Eastern European region., Objective: The purpose of this paper is to examine consumer acceptance of genetic-based personalized nutrition in Hungary. Therefore a national representative survey was conducted involving 1000 individuals. The starting point of the model used is the assumption that the consumer acceptance of personalized nutrition is influenced by its consumer perceptions, which are affected by psychological processes that, in a more general sense, determine acceptance of food innovations., Results: The results show that 23.5% of respondents accept genetic test-based personalized nutrition. Women were found to reject the new technology in a significantly smaller proportion than men. The relationship between other demographic variables (i.e. age groups, education and subjective income level) and the perception of genetic-based personalized nutrition is also significant. Our results indicate that it is perceived cost/benefit that is most strongly related to genetically based personalized dietary preferences, followed by perceived risk and subjective norms. Perceived uncertainty and perceived behavioural control, however, have only a weak relationship with genetic-based personalized dietary preferences., Conclusions: Compared with the magnitude of the effect of socio-demographic criteria, it can be concluded that, on the whole, psychological processes in the individual have a greater influence on the development of preferences for genetic-based personalized nutrition than any socio-demographic factor. This also confirms the trend that there are more and more value-added products or value propositions (where a significant part of the value added is to be found in product innovation), for which psychological characteristics are/should be given more emphasis among the segmentation criteria.

IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1β in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1β. Inflammasome-independent IL1β release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1β was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1β allowed intratumoral accumulation of CD8 + effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8 + T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8 + T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1β through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors., (©2020 American Association for Cancer Research.)

Background: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker., Methods: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models., Results: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4 + and CD8 + T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs., Conclusions: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy., Competing Interests: Competing interests: HR and EA are employees of Oncurious NV. PM is a consultant to Oncurious NV., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

This study reports the long-term storage stability of a formulation of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The F3-formulated DMTS was stored in glass ampules at 4, 22, and 37 °C. Over a period of one year, nine ampules ( n = 3 at each temperature) were analyzed by high-performance liquid chromatography (HPLC)-UV/vis at daily time intervals in the first week, weekly time intervals in the first month, and monthly thereafter for a period of one year to determine the DMTS content. No measurable loss of DMTS was found at 4 and 22 °C, and good stability was noted up to five months for samples stored at 37 °C. At 37 °C, a 10% (M/M) decrease of DMTS was discovered at the sixth month and only 30% (M/M) of DMTS remained by the end of the study; discoloration of the formulation and the growth of new peaks in the HPLC chromatogram were also observed. To identify the unknown peaks at 37 °C, controlled oxidation studies were performed on DMTS using two strong oxidizing agents: meta -chloroperoxybenzoic acid ( m CPBA) and hydrogen peroxide (H 2 O 2 ). Dimethyl tetrasulfide and dimethyl pentasulfide were observed as products using both of the oxidizing agents. Dimethyl disulfide was also observed as a product of degradation, which was further oxidized to S -methyl methanethiosulfonate only when m CPBA was used. HPLC-UV/vis and gas chromatography-mass spectrometry/solid phase microextraction analysis revealed good agreement between the degradation products of the stability study at 37 °C and those of disproportionation reactions. Furthermore, at 4 and 22 °C, chromatograms were remarkably stable over the one-year study period, indicating that the F3-formulated DMTS shows excellent long-term storage stability at T ≤ 22 °C., Competing Interests: The authors declare the following competing financial interest(s): Two patents by two coauthors, related to DMTS are: (1) Gary A. Rockwood, Ilona Petrikovics (SHSU) and Steven I. Baskin (USAMRICD): Dimethyl Trisulfide as a Cyanide Antidote. U.S. Patent No. 9,375,407, 2016, (2) Ilona Petrikovics and Kristof Kovacs (SHSU). Formulations of Dimethyl Trisulfide for Use as a Cyanide Antidote. U.S. Patent No. 9,456,996, 2016., (© 2020 American Chemical Society.)

Monocytes influence multiple aspects of tumor progression, including antitumor immunity, angiogenesis, and metastasis, primarily by infiltrating tumors, and differentiating into tumor-associated macrophages. Emerging evidence suggests that the tumor-induced systemic environment influences the development and phenotype of monocytes before their arrival to the tumor site. As a result, circulating monocytes show functional alterations in cancer, such as the acquisition of immunosuppressive activity and reduced responsiveness to inflammatory stimuli. In this review, we summarize available evidence about cancer-induced changes in monopoiesis and its impact on the abundance and function of monocytes in the periphery. In addition, we describe the phenotypical alterations observed in tumor-educated peripheral blood monocytes and highlight crucial gaps in our knowledge about additional cellular functions that may be affected based on transcriptomic studies. We also highlight emerging therapeutic strategies that aim to reverse cancer-induced changes in monopoiesis and peripheral monocytes to inhibit tumor progression and improve therapy responses. Overall, we suggest that an in-depth understanding of systemic monocyte reprogramming will have implications for cancer immunotherapy and the development of clinical biomarkers., (Copyright © 2020 Kiss, Caro, Raes and Laoui.)

Background: For ICD-11, the WHO emphasized the clinical utility of communication and the need to involve service users and carers in the revision process., Aims: The objective was to assess whether medical vocabulary was accessible, which kinds of feelings it activated, whether and how users and carers would like to rephrase terms, and whether they used diagnosis to talk about mental health experiences., Method: An innovative protocol focused on two diagnoses (depressive episode and schizophrenia) was implemented in 15 different countries. The same issues were discussed with users and carers: understanding, feelings, rephrasing, and communication., Results: Most participants reported understanding the diagnoses, but associated them with negative feelings. While the negativity of "depressive episode" mostly came from the concept itself, that of "schizophrenia" was largely based on its social impact and stigmatization associated with "mental illness". When rephrasing "depressive episode", a majority kept the root "depress*", and suppressed the temporal dimension or renamed it. Almost no one suggested a reformulation based on "schizophrenia". Finally, when communicating, no one used the phrase "depressive episode". Some participants used words based on "depress", but no one mentioned "episode". Very few used "schizophrenia"., Conclusion: Data revealed a gap between concepts and emotional and cognitive experiences. Both professional and experiential language and knowledge have to be considered as complementary. Consequently, the ICD should be co-constructed by professionals, service users, and carers. It should take the emotional component of language, and the diversity of linguistic and cultural contexts, into account.

Over the past decade, cancer immunotherapy has been steering immune responses toward cancer cell eradication. However, these immunotherapeutic approaches are hampered by the tumor-promoting nature of myeloid cells, including monocytes, macrophages, and neutrophils. Despite the arsenal of defense strategies against foreign invaders, myeloid cells succumb to the instructions of an established tumor. Interestingly, the most primordial defense responses employed by myeloid cells against pathogens, such as complement activation, antibody-dependent cell cytotoxicity and phagocytosis, actually seem to favor cancer progression. In this review, we discuss how rudimentary defense mechanisms deployed by myeloid cells can promote tumor progression., (Copyright © 2020 Lebegge, Arnouk, Bardet, Kiss, Raes and Van Ginderachter.)

We demonstrate the design, fabrication, and experimental characterization of near-field binary phase transmission diffractive optical elements (DOEs) in single crystal diamond. Top-hat and arbitrary pattern DOE beam shapers were numerically optimized using an iterative Fourier transform algorithm (IFTA). Commercially available single crystal diamond plates (3 m m ×3 m m ×0.3 m m ) were patterned using hardmask deposition ( α -Si), e-beam lithography, and O 2 plasma-based diamond reactive ion etching. The resulting binary phase relief patterns were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Experimental characterization of the single crystal diamond DOEs in transmission at λ =532 n m confirms excellent uniformity of the resulting top-hat beam profile as required in copper welding applications.

Background and Purpose: Pre-surgical functional MRI (fMRI) is an important modality of examinations before brain surgery. There are several artefacts (e.g. motion, susceptibility) which may hinder the evaluation of fMRI data. Physiological artefacts (breathing, pulsation) also affect the sensitivity and specificity of anatomical localization. The aim of this study is to demonstrate the efficiency of physiological artefact identification and removal methods for presurgical evaluation., Methods: Siemens Magnetom Verio 3T MRI scanner was used to collect data. The physiological parameters (breathing, pulse) were recorded with the MRI system's built-in devices. Data from fourteen patients - with primary brain tumour - were evaluated with SPM12 utilizing the RETROICOR/RVHR tool to detect and decrease the effect of physiological artefacts. We compared the statistical maps obtained with and without the physiological correction using the Jaccard similarity coefficient, and ROI analyses., Results: Significant differences were found in the mean ROI values (p<0.0016) and the extensions of eloquent activations (p<0.0013), when using the physiological correction (RETORICOR/RVHR) based on convolution method. On the other hand, no significant differences were found between the ROIs' standard deviations (F=0.28). The RETROICOR/ RVHR method helps to define the precise localisation of eloquent areas (p<0.009). The number of irrelevant (non-significant) voxels were increased (p<0.001). ., Conclusion: Minimising of physiological artefacts in fMRI data calculations, the (RETROICOR/RVHR) method based on convolution has been successfully adapted. This algorithm could be helpful before neurosurgical intervention. The activity pattern became more reliable.

Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen ( COL4A1 ) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker-Warburg Syndrome or Muscle-Eye-Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations arise by transitions in glycine triplets, associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy, and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in RNA-inhibitory Drosophila . Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres.

We demonstrate a novel method for fabricating single crystal diamond diffraction gratings based on crystallographic etching that yields high-quality diffraction gratings from commercially available <100> diamond plates. Both V-groove and rectangular gratings were fabricated and characterised using scanning electron microscopy and atomic force microscopy, revealing angles of 57° and 87° depending on the crystal orientation, with mean roughness below R a = 5 nm on the sidewalls. The gratings were also optically characterised, showing good agreement with simulated results. The fabrication method demonstrated in this contribution shows the way for manufacturing high-quality diamond diffractive components that surpass existing devices both in quality and manufacturability.

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA-oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

Introduction: Alzheimer's disease (AD) is the leading cause of cognitive decline. Epilepsy is a frequent comorbid condition of AD. While previous studies analyzed the risk factors of AD-related epileptic seizures, we still lack biomarkers of epilepsy in mild AD cases. Purpose: The aim of our study was to analyze the correlations between neuropsychology, cortical thickness, and brain volumetric measurements in mild Alzheimer patients with concomitant epileptic seizures. Materials and methods: We selected mild AD patients from our database to examine them with structural magnetic resonance imaging, 24 h electroencephalography, and detailed neuropsychology. We made the diagnosis of epilepsy based on epileptology data including neurophysiology. We retrospectively analyzed the neuropsychology pattern, clinical and epidemiologic features, cortical thickness, and volumetric values of mild AD patients with and without overt clinical seizures using covariance weighted general linear model. Results: We found epileptic seizures in 26% of mild AD patients. Patients with seizures performed worse in visuo-spatial scores than patients without ( p = 0.003). Patients with seizures had smaller parietal thickness ( p = 0.018), being associated to reduced thickness of left ( p = 0.007), and right precunei ( p = 0.005). The visuo-spatial performance positively and strongly correlated with the thickness of the parietal lobe ( r = 0.67; p = 0.002) and with the volume of the precuneus ( r = 0.612; p = 0.005). Conclusion: Epileptic seizures are common even in mild AD. We found that a prominent deficit in visuo-spatial skills is a red flag for epileptic seizures in the initial phase of AD, indicating the early involvement of parietal lobe in the neurodegenerative process. Because our findings suggest that the degeneration of precuneus is a sensitive marker of seizures associated to mild AD, clinicians need to pay special attention to the pattern of atrophy shown by structural MRI. Our results confirm previous data suggesting that epileptic seizures might be associated to a faster progressing type of AD with the early degeneration of posterior cortical areas.

Participating or winning a medal in major track and field (athletics) competitions is the goal of every athlete. However, health problems can impair sports performance and affect this dream. Therefore, we present ten tips to help hurdle the challenges of illness/injury at major athletics championships: (1) Prepare for travel (medical checking, vaccine, time-zone, jet lag, culture, food habits…), (2) Respect athlete characteristics and discipline specificity (sex, endurance/explosive), (3) Educate athletes and their entourages regarding prevention, (4) Vigilance of painful symptoms and subclinical illness markers, (5) Avoid infection risk (washing hands, safe food and drink, avoid contact with sick people…), (6) Train appropriately and optimally (physical conditioning, technical training, load management, and psychological preparation), (7) Health status (history of previous injuries, well-being in the month before championships), (8) Lifestyle (good sleep, regular hydration and nutrition with safe water/food, regular fruits and vegetables, improve recovery strategies…), (9) Environmental considerations (heat, cold, air cleaning, changes or climatic conditions…), (10) Safety (equipment, rules, own-practice in athletics, and extra-sport activities). These ten tips "PREVATHLES" are based on our field experience in addition to existing epidemiological and experimental literature in athletics and other sports. Although there is currently no scientific evidence for their efficacy, sound judgement, and logical practice provide a strong basis, and given the low risk of using them in the benefit/risk balance, we suggest athletes and those around them follow these ten tips to limit the impact of injury/illness on championship performance., (Copyright © 2019 Edouard, Richardson, Murray, Duncan, Glover, Kiss, Depiesse and Branco.)

It is a clinical experience that acute lesions of the cerebellum induce pathological tremor, which tends to improve. However, quantitative characteristics, imaging correlates, and recovery of cerebellar tremor have not been systematically investigated. We studied the prevalence, quantitative parameters measured with biaxial accelerometry, and recovery of pathological tremor in 68 patients with lesions affecting the cerebellum. We also investigated the correlation between the occurrence and characteristics of tremor and lesion localization using 3D T1-weighted MRI images which were normalized and segmented according to a spatially unbiased atlas template for the cerebellum. Visual assessment detected pathological tremor in 19% while accelerometry in 47% of the patients. Tremor was present both in postural and intentional positions, but never at rest. Two types of pathological tremor were distinguished: (1) low-frequency tremor in 36.76% of patients (center frequency 2.66 ± 1.17 Hz) and (2) normal frequency-high-intensity tremor in 10.29% (center frequency 8.79 ± 1.43 Hz). The size of the lesion did not correlate with the presence or severity of tremor. Involvement of the anterior lobe and lobule VI was related to high tremor intensity. In all followed up patients with acute cerebellar ischemia, the tremor completely recovered within 8 weeks. Our results indicate that cerebellar lesions might induce pathological postural and intentional tremor of 2-3 Hz frequency. Due to its low frequency and low amplitude, quantitative tremorometry is neccessary to properly identify it. There is no tight correlation between lesion localization and quantitative characteristics of cerebellar tremor.