Репозиторий Университета

Background: There is currently a wide therapeutic arsenal for migraine patients, without a single first-line preventive drug and we choose the different available alternatives taking into account comorbidities, national guidelines, previous treatments and personal experiences. Our objective was to evaluate the differences in the use of migraine treatments between neurologists from different countries. Methods: This is a multi-centre observational study carried out by neurologists from specialized headache units in seven countries, retrospective with consecutive inclusion of all patients presenting with a migraine diagnosis, over a period of three months. Results: A total of 734 patients were recruited but only 600 were considered in the analysis in order to homogenize the patient cohorts from countries: 200 Spain (ES), 100 Italy (IT), 85 Russia (RUS), 80 Germany (DE), 60 Portugal (PT), 45 Poland (PL) and 30 Australia (AU). 85.4 % of patients were women with a mean age of 42.6 ± 11.8 years. Considering previous and current preventive treatment, the order of use was: antidepressants (69.3 %), antiepileptic drugs (54.7 %), beta-blockers and antihypertensive drugs (49.7 %), OnabotulinumtoxinA (44.0 %) and others (36.2 %). Statistically significant differences were found between all pharmacological classes: antidepressants were commonly used in all countries, with the exception of Poland (AU: 76.7 %, IT: 71.0 %, DE: 60.0 %, PL: 31.1 %, PT: 71.7 %, RUS: 70.6 %, ES: 78.5 %; p < 0.0001); antiepileptic drugs were more frequently prescribed in Portugal, Australia and Spain (AU: 73.3 %, IT: 40.0 %, DE: 37.5 %, PL: 48.9 %, PT: 85.0 %, RUS: 29.4 % and ES: 69.0 %; p < 0.0001); beta-blockers and antihypertensive drugs were frequently used in all countries except Italy (AU: 60.0 %, IT: 14.0 %, DE: 53.8 %, PL: 48.9 %, PT: 68.3 %, RUS: 49.4 % and ES: 59.0 %; p < 0.0001); BTX-A were predominately used in Spain, Italy and Australia (AU:56.7 %, IT:58.0 %, DE:20.0 %, PL: 42.2 %, PT: 26.7 %, RUS: 24.7 % and ES: 58.5 %; p < 0.0001) and others were most frequently used in Poland (AU: 0.0 %, IT: 19.0 %, DE: 42.5 %, PL: 95.6 %, PT: 31.7 %, RUS: 3.5 % and ES: 49.5 %; p < 0.0001). If only patients without comorbidities are considered (200/600), statistically differences between countries persist in all preventive treatments. Conclusions: There is heterogeneity in the choice of preventive treatment between different countries. Prospective comparative studies of the different oral and subcutaneous alternatives would help to create a global therapeutic algorithm that would guarantee the best option for our patients.

Recently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around the world. However, reports have shown that the main populations of the transplanted MSCs are trapped in the liver, spleen, and lung upon administration, highlighting the importance of the development of cell-free therapies. Concerning rising evidence suggesting that the beneficial effects of MSC therapy are closely linked to MSC-released components, predominantly MSC-derived exosomes, the development of an MSC-based cell-free approach is of paramount importance. The exosomes are nano-sized (30–100 nm) lipid bilayer membrane vesicles, which are typically released by MSCs and are found in different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, and bioactive lipids, thus showing pronounced therapeutic competence for tissues recovery through the maintenance of their endogenous stem cells, the enhancement of regenerative phenotypic traits, inhibition of apoptosis concomitant with immune modulation, and stimulation of the angiogenesis. Conversely, the specific roles of MSC exosomes in the treatment of various tumors remain challenging. The development and clinical application of novel MSC-based cell-free strategies can be supported by better understanding their mechanisms, classifying the subpopulation of exosomes, enhancing the conditions of cell culture and isolation, and increasing the production of exosomes along with engineering exosomes to deliver drugs and therapeutic molecules to the target sites. In the current review, we deliver a brief overview of MSC-derived exosome biogenesis, composition, and isolation methods and discuss recent investigation regarding the therapeutic potential of MSC exosomes in regenerative medicine accompanied by their double-edged sword role in cancer.

Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as “purinergic signalling”. Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

Background: Lifting The Burden (LTB) and European Headache Federation (EHF) have developed a set of headache service quality indicators, successfully tested in specialist headache centres. Their intended application includes all levels of care. Here we assess their implementation in primary care. Methods: We included 28 primary-care clinics in Germany (4), Turkey (4), Latvia (5) and Portugal (15). To implement the indicators, we interviewed 111 doctors, 92 nurses and medical assistants, 70 secretaries, 27 service managers and 493 patients, using the questionnaires developed by LTB and EHF. In addition, we evaluated 675 patients’ records. Enquiries were in nine domains: diagnosis, individualized management, referral pathways, patient education and reassurance, convenience and comfort, patient satisfaction, equity and efficiency of headache care, outcome assessment and safety. Results: The principal finding was that Implementation proved feasible and practical in primary care. In the process, we identified significant quality deficits. Almost everywhere, histories of headache, especially temporal profiles, were captured and/or assessed inaccurately. A substantial proportion (20%) of patients received non-specific ICD codes such as R51 (“headache”) rather than specific headache diagnoses. Headache-related disability and quality of life were not part of routine clinical enquiry. Headache diaries and calendars were not in use. Waiting times were long (e.g., about 60 min in Germany). Nevertheless, most patients (> 85%) expressed satisfaction with their care. Almost all the participating clinics provided equitable and easy access to treatment, and follow-up for most headache patients, without unnecessary barriers. Conclusions: The study demonstrated that headache service quality indicators can be used in primary care, proving both practical and fit for purpose. It also uncovered quality deficits leading to suboptimal treatment, often due to a lack of knowledge among the general practitioners. There were failures of process also. These findings signal the need for additional training in headache diagnosis and management in primary care, where most headache patients are necessarily treated. More generally, they underline the importance of headache service quality evaluation in primary care, not only to identify-quality failings but also to guide improvements. This study also demonstrated that patients’ satisfaction is not, on its own, a good indicator of service quality.

Background: SARS-CoV-2 reached Europe in early 2020 and disrupted the private and public life of its citizens, with potential implications for substance use. The objective of this study was to describe possible changes in substance use in the first months of the SARS-CoV-2 pandemic in Europe. Methods: Data were obtained from a cross-sectional online survey of 36,538 adult substance users from 21 European countries conducted between April 24 and July 22 of 2020. Self-perceived changes in substance use were measured by asking respondents whether their use had decreased (slightly or substantially), increased (slightly or substantially), or not changed during the past month. The survey covered alcohol (frequency, quantity, and heavy episodic drinking occasions), tobacco, cannabis, and other illicit drug use. Sample weighted data were descriptively analysed and compared across substances. Results: Across all countries, use of all substances remained unchanged for around half of the respondents, while the remainder reported either a decrease or increase in their substance use. For alcohol use, overall, a larger proportion of respondents indicated a decrease than those reporting an increase. In contrast, more respondents reported increases in their tobacco and cannabis use during the previous month compared to those reporting decreased use. No distinct direction of change was reported for other substance use. Conclusions: Our findings suggest changes in use of alcohol, tobacco and cannabis during the initial months of the pandemic in several European countries. This study offers initial insights into changes in substance use. Other data sources, such as sales statistics, should be used to corroborate these preliminary findings.

Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition.

Background: Confinement due to COVID-19 has increased mental ill-health. Few studies unpack the risk and protective factors associated with mental ill-health and addictions that might inform future preparedness. Methods: Cross-sectional on-line survey with 37,810 Catalan residents aged 16+ years from 21 April to 20 May 2020 reporting prevalence of mental ill-health and substance use and associated coping strategies and behaviours. Results: Weighted prevalence of reported depression, anxiety and lack of mental well-being was, respectively, 23, 26, and 75%, each three-fold higher than before confinement. The use of prescribed hypnosedatives was two-fold and of non-prescribed hypnosedatives ten-fold higher than in 2018. Women, younger adults and students were considerably more likely, and older and retired people considerably less likely to report mental ill-health. High levels of social support, dedicating time to oneself, following a routine, and undertaking relaxing activities were associated with half the likelihood of reported mental ill-health. Worrying about problems living at home, the uncertainty of when normality would return, and job loss were associated with more than one and a half times the likelihood of mental ill-health. With the possible exception of moderately severe and severe depression, length of confinement had no association with reported mental ill-health. Conclusions: The trebling of psychiatric symptomatology might lead to either to under-identification of cases and treatment gap, or a saturation of mental health services if these are not matched with prevalence increases. Special attention is needed for the younger adult population. In the presence of potential new confinement, improved mental health literacy of evidence-based coping strategies and resilience building are urgently needed to mitigate mental ill-health.

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell’s history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells.

In recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations.

Considering the central role of inflammation in the pathogenesis of periodontitis, the combination of NSPT with different agents that can modulate the host immune-inflammatory response has been proposed to enhance the outcomes of NSPT. The aim of this paper is to systematically review the literature on the efficacy of systemic host modulators (HMs) as adjuncts to non-surgical periodontal therapy (NSPT) in improving pocket depth (PD) reduction and clinical attachment level (CAL) gain in healthy and systemically compromised patients. RCTs with ≥ 3 months follow-up were independently searched by two reviewers. Meta-analysis was performed when ≥ 3 studies on the same HM were identified. The quality of the evidence was rated according to the GRADE approach to rate the certainty of evidence. 38 articles were included in the qualitative assessment and 27 of them were included in the meta-analysis. There is low/very low evidence that the adjunctive use of sub-antimicrobial dose of doxycicline, melatonin and the combination of omega-3 and low dose aspirin (in type 2 diabetic patients) to NSPT would improve PD and/or CAL. Conflicting evidence is available on the efficacy of probiotics. Future studies controlling for confounding factors, using composite outcomes to define the endpoint of therapy and considering not only the patient- but also as the site-specific effect of systemic HMs are warranted. The dosage, posology and long-term effect of HMs still need to be clarified, also in association to the presence of systemic conditions potentially affecting the response to HMs administration.

Background: It remains unclear whether alcohol use disorders (AUDs) can be characterized by specific levels of average daily alcohol consumption. The aim of the current study was to model the distributions of average daily alcohol consumption among those who consume alcohol and those with alcohol dependence, the most severe AUD, using various clustering techniques. Methods: Data from Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were used in the current analyses. Clustering algorithms were applied in order to group a set of data points that represent the average daily amount of alcohol consumed. Gaussian Mixture Models (GMMs) were then used to estimate the likelihood of a data point belonging to one of the mixture distributions. Individuals were assigned to the clusters which had the highest posterior probabilities from the GMMs, and their treatment utilization rate was examined for each of the clusters. Results: Modeling alcohol consumption via clustering techniques was feasible. The clusters identified did not point to alcohol dependence as a separate cluster characterized by a higher level of alcohol consumption. Among both females and males with alcohol dependence, daily alcohol consumption was relatively low. Conclusions: Overall, we found little evidence for clusters of people with the same drinking distribution, which could be characterized as clinically relevant for people with alcohol use disorders as currently defined.

Background: Malaria is a disease annually causing over 400,000 deaths. Deep understanding of molecular and genetic processes underlying its life cycle and pathogenicity is required to efficiently resist it. RNA interference is a mechanism of the gene expression regulation typical for a wide variety of species. Even though the existence of this phenomenon in Plasmodium falciparum has long been rejected, several recent works pose hypotheses and provide direct and indirect evidence of the existence of mechanisms similar to RNA interference in this organism. In particular, the possibility of regulation of P. falciparum gene expression through human microRNAs is of great importance both for fundamental biology and for medicine. In the present work we address the problem of possibility of the existence in the P. falciparum genome of the nucleotide sequences such that mRNAs transcribed from genes containing these sequences could form duplexes with human microRNAs. Using bioinformatics methods we have analysed genomes of 15 P. falciparum isolates for sequences homological to these microRNAs. Results: The analysis has demonstrated the existence of a vast number of genes that could potentially be regulated by the human microRNAs in the plasmodial genome. Conclusions: Despite the fact that the numbers of homological intervals vary significantly between isolates, the hsa-miR-451a and hsa-miR-223-3p microRNAs are expected to make the most notable contribution to the pathogenesis of P. falciparum malaria. The majority of homological intervals occur in genes encoding cell adhesion proteins.

Background: The aim of this paper was to systematically review the root canal configuration (RCC) and morphology literature of the mandibular second premolar (Mn2P). Methods: Systematic research of five electronic databases was performed to identify published literature concerning the root canal configuration (RCC) of the Mn2P up through July 2020. Studies were selected according to predefined search terms and keywords inclusion criteria: “root canal configuration”, “root canal system”, “root canal morphology”, “mandibular second premolar”, “mandibular premolars”, “morphology” and “anatomy”. Further possible studies were identified by cross-referencing and screening the bibliographies of the selected articles. Results: From 1622 retrieved studies, 44 studies investigating the internal morphology of 17,839 Mn2Ps were included. Most examined Mn2Ps were single-rooted (89.5–100%); two-rooted (0.1–8%) and three-rooted (0.1–3.5%) Mn2Ps at lower frequency. Most frequent RCCs reported were 1–1–1/1 (55.3–99.6%) followed by 1–1–2/2 (0.5–57%) and 2–2–2/2 (0.6–18%). The meta-analysis of seven studies demonstrated that a significantly higher number of RCC type 1–2–1/1 (OR [95%CI] = 2.05 [1.27, 3.33]) and 2–2–2/2 (OR [95%CI] = 2.32 [0.65, 8.63]) were observed in male than in female patients. Conclusions: Different RCC research methods have been reported. Whereas clearing and radiographs were commonly used in the past, CBCT has been prevalent in recent years. A globally high frequency of a 1–1–1/1 RCC in the Mn2P has been reported. Nevertheless, the probability that different, more complicated RCCs can appear in Mn2Ps should not be underestimated and, thus, should be taken into consideration when making decisions during an endodontic treatment.

Background: The existing data demonstrate the potential role of trace elements in nasal mucociliary clearance, although the association between trace element and mineral status and ciliary function in children with chronic rhinosinusitis is insufficiently studied. Therefore, the objective of the present study is evaluation of trace element and mineral status and mucociliary function in pediatric CRS patients before and after functional endoscopic sinus surgery. Methods: The present study involved 30 children with chronic rhinosinusitis without nasal polyps. During this follow-up the patients were examined preoperatively (point 0), underwent functional endoscopic sinus surgery, and were repeatedly examined at three months postoperatively (point 1). At both points the patients were subjected to quality-of-life assessment using SNOT-20 questionnaire; endoscopic and computer tomography examination of the nasal sinuses; evaluation of ciliary function and mucosal cytology using high-speed videomicroscopy; assessment of blood count and inflammatory markers; as well as analysis of trace element and mineral levels in whole blood, serum, and hair using inductively-coupled plasma mass-spectrometry. Results: The obtained data demonstrate that endoscopic sinus surgery significantly improved sinonasal pathology in children with chronic rhinosinusitis, as evidenced by significantly reduced Lund-Mackay, Lund-Kennedy, and SNOT-20 scores. At the same time, no significant improvement of ciliary functions or mucosal cytology was observed postoperatively. Trace element status assessment demonstrated that postoperative serum Zn, whole blood Mg and Cu were significantly lower as compared to preoperative values. In contrast, serum Mn and Cr, as well as whole blood Cr and hair Se were characterized by a significant increase at three months postoperatively. Multiple linear regression analysis demonstrated that serum Zn is significantly associated with the number of ciliated cells and cell viability, whereas serum Mn and whole blood Cu concentrations are inversely associated with cell viability and ciliary length, respectively. Hair Se was found to be associated with the number of neutrophils in the mucosa biopsy. Conclusion: Redistribution of trace elements and minerals may at least partially mediate prolonged recovery of mucosal ciliary function in children with chronic rhinosinusitis in three months after functional sinus surgery, although the particular mechanisms of these alterations in trace element levels are to be discovered.

Collective cooperation is essential to human society, and it exists in many social dilemmas. In the scenario of a collective-risk social dilemma, a group of players have to collectively contribute to a public fund to prevent the tragedy of the commons, such as dangerous climate change, because everybody will lose all their remaining money when the damage happens with a certain probability if the group fails to reach a fixed fundraising target. Yet, it remains largely unclear how the group size affects the probability of reaching the collective target and the mechanism that drives different outcomes of the collective cooperation. Here, we contribute to the literature by exploring the role of group size in the collective-risk social dilemma and the potential underlying mechanism using both model simulations and human experiments. Through simulations we found that the rate of failure for collective cooperation increases for larger groups, along with the arising of bystander effect and a decrease in average contributions, which are confirmed by our experimental observations. We further analyze the patterns of investment behaviors in the experiment setting by categorizing players into cooperators, altruists, and free riders using both a clustering method and a golden standard. We found that altruists who tend to contribute more, rather than cooperators who prefer contributing a fair-share investment, play a crucial role in groups with success outcome in early and/or middle stages of the game. Our results indicate that bystanders are dynamic and their amount depends on the contribution of others. When others contribute less, bystanders also contribute less. If the collective goal is unlikely to achieve, more players choose to be bystanders who strategically contribute less, intriguing the failure of the collective goal. Our findings suggest a potentially effective way to solve the collective-risk social dilemma by reducing the bystander effect through the mechanism design of forming small groups.

Background: The existing data demonstrate the potential role of trace elements in nasal mucociliary clearance, although the association between trace element and mineral status and ciliary function in children with chronic rhinosinusitis is insufficiently studied. Therefore, the objective of the present study is evaluation of trace element and mineral status and mucociliary function in pediatric CRS patients before and after functional endoscopic sinus surgery. Methods: The present study involved 30 children with chronic rhinosinusitis without nasal polyps. During this follow-up the patients were examined preoperatively (point 0), underwent functional endoscopic sinus surgery, and were repeatedly examined at three months postoperatively (point 1). At both points the patients were subjected to quality-of-life assessment using SNOT-20 questionnaire; endoscopic and computer tomography examination of the nasal sinuses; evaluation of ciliary function and mucosal cytology using high-speed videomicroscopy; assessment of blood count and inflammatory markers; as well as analysis of trace element and mineral levels in whole blood, serum, and hair using inductively-coupled plasma mass-spectrometry. Results: The obtained data demonstrate that endoscopic sinus surgery significantly improved sinonasal pathology in children with chronic rhinosinusitis, as evidenced by significantly reduced Lund-Mackay, Lund-Kennedy, and SNOT-20 scores. At the same time, no significant improvement of ciliary functions or mucosal cytology was observed postoperatively. Trace element status assessment demonstrated that postoperative serum Zn, whole blood Mg and Cu were significantly lower as compared to preoperative values. In contrast, serum Mn and Cr, as well as whole blood Cr and hair Se were characterized by a significant increase at three months postoperatively. Multiple linear regression analysis demonstrated that serum Zn is significantly associated with the number of ciliated cells and cell viability, whereas serum Mn and whole blood Cu concentrations are inversely associated with cell viability and ciliary length, respectively. Hair Se was found to be associated with the number of neutrophils in the mucosa biopsy. Conclusion: Redistribution of trace elements and minerals may at least partially mediate prolonged recovery of mucosal ciliary function in children with chronic rhinosinusitis in three months after functional sinus surgery, although the particular mechanisms of these alterations in trace element levels are to be discovered.

Collective cooperation is essential to human society, and it exists in many social dilemmas. In the scenario of a collective-risk social dilemma, a group of players have to collectively contribute to a public fund to prevent the tragedy of the commons, such as dangerous climate change, because everybody will lose all their remaining money when the damage happens with a certain probability if the group fails to reach a fixed fundraising target. Yet, it remains largely unclear how the group size affects the probability of reaching the collective target and the mechanism that drives different outcomes of the collective cooperation. Here, we contribute to the literature by exploring the role of group size in the collective-risk social dilemma and the potential underlying mechanism using both model simulations and human experiments. Through simulations we found that the rate of failure for collective cooperation increases for larger groups, along with the arising of bystander effect and a decrease in average contributions, which are confirmed by our experimental observations. We further analyze the patterns of investment behaviors in the experiment setting by categorizing players into cooperators, altruists, and free riders using both a clustering method and a golden standard. We found that altruists who tend to contribute more, rather than cooperators who prefer contributing a fair-share investment, play a crucial role in groups with success outcome in early and/or middle stages of the game. Our results indicate that bystanders are dynamic and their amount depends on the contribution of others. When others contribute less, bystanders also contribute less. If the collective goal is unlikely to achieve, more players choose to be bystanders who strategically contribute less, intriguing the failure of the collective goal. Our findings suggest a potentially effective way to solve the collective-risk social dilemma by reducing the bystander effect through the mechanism design of forming small groups.

Nearly half of patients with prostate cancer (PCa) harbour low- or intermediate-risk disease considered suitable for active surveillance (AS). However, up to 44% of patients discontinue AS within the first five years, highlighting the unmet clinical need for robust baseline risk-stratification tools that enable timely and accurate prediction of tumour progression. In this proof-of-concept study, we sought to investigate the added value of MRI-derived radiomic features to standard-of-care clinical parameters for improving baseline prediction of PCa progression in AS patients. Tumour T2-weighted imaging (T2WI) and apparent diffusion coefficient radiomic features were extracted, with rigorous calibration and pre-processing methods applied to select the most robust features for predictive modelling. Following leave-one-out cross-validation, the addition of T2WI-derived radiomic features to clinical variables alone improved the area under the ROC curve for predicting progression from 0.61 (95% confidence interval [CI] 0.481–0.743) to 0.75 (95% CI 0.64–0.86). These exploratory findings demonstrate the potential benefit of MRI-derived radiomics to add incremental benefit to clinical data only models in the baseline prediction of PCa progression on AS, paving the way for future multicentre studies validating the proposed model and evaluating its impact on clinical outcomes.

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.