The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.

• MeSH
• Longevity * physiology   MeSH
• Cardiovascular Diseases physiopathology   epidemiology   MeSH
• Humans MeSH
• Oxidative Stress physiology   MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aging * physiology   MeSH
• Gastrointestinal Microbiome physiology   MeSH
• Healthy Aging physiology   MeSH
• Life Style MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Introduction. Vagal nerve stimulation (VNS) is a therapeutical option for the treatment of drug-resistant epileptic patients. The response to VNS varies from patient to patient and is difficult to predict. The proposed study is based on our previous work, identifying relative mean power in pre-implantation EEG as a reliable marker for VNS efficacy prediction in adult patients. Our study has two main tasks. Firstly, to confirm the utility of relative mean power as a feature correlating with VNS efficacy in children. The second is to validate the applicability of our prediction classifier, Pre-X-Stim, in the pediatric population. Material and Methods. We identified a group of children with drug-resistant epilepsy. We included only children in whom EEG contained photic stimulation (Task 1) or was recorded based on the defined acquisition protocol used for development Pre-X-Stim (Task 2). Relative mean powers were calculated. VNS responders and non-responders were compared based on relative mean powers' values. In the next step, we evaluate the utility of our classifier, Pre-X-Stim, in the children population. Results: We identified 57 children treated with VNS - 17 patients were recruited for the Task 1 and 7 patients for the Task 2. When focusing on relative mean powers in EEG spectra, we observed statistically significant differences in theta range. The Pre-X-Stim algorithm was able to predict VNS efficacy correctly in 6 out of 7 patients (the accuracy 83.3%, the sensitivity 75%, the specificity 100%). Conclusions. Based on our results, it seems that children and adults share a similar pattern of EEG relative mean power changes. These changes can be used for pre-implantation prediction of VNS efficacy.

• MeSH
• Child MeSH
• Electroencephalography * methods   MeSH
• Epilepsy * therapy   physiopathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Drug Resistant Epilepsy * therapy   physiopathology   MeSH
• Scalp MeSH
• Vagus Nerve Stimulation * methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Several studies have demonstrated the positive effects of mindfulness and self-compassion on employee well-being, mental health, and resilience. The objective of this observational study was to explore the mutual relationships among the dimensions of self-compassion and particular characteristics of work-related well-being: work engagement, workaholism (excessive and compulsive work), and job boredom in a population of early career workers. In this quantitative cross-sectional study, 286 master's students with proper working experience were examined; results from 244 respondents were suitable for further data analysis. The Self-compassion Scale, Utrecht Work Engagement Scale, Dutch Work Addiction Scale, and Dutch Boredom Scale were administered. Spearman's rank correlation analysis found a positive relationship between work engagement and excessive work and a negative relationship between work engagement and job boredom. Furthermore, a positive correlation was identified between compulsive work and negative subscales of the Self-compassion Scale. Structural equation modeling indicated that workaholism was a mediator between the negative scales of self-compassion and work engagement with job boredom. In conclusion, the negative aspects of self-compassion (isolation, self-judgment, and over-identification) are related to the symptoms of workaholism in young workers. Self-compassion-based interventions could help prevent the negative effects of compulsive and excessive work. Possible age-related explanations for the positive relationship between work engagement and workaholism (i.e., excessive work) are discussed. Future longitudinal research could identify the dynamics of the connection between self-compassion and work-related well-being from a long-term perspective.

• Publication type
• Journal Article MeSH

AIMS: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. METHODS: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. RESULTS: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. CONCLUSIONS: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

• MeSH
• Adult MeSH
• Phenotype MeSH
• Genotype MeSH
• Hospitalization MeSH
• Pharmaceutical Preparations metabolism   MeSH
• Drug Interactions MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged MeSH
• Cytochrome P-450 Enzyme System * genetics   metabolism   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: A multicomponent meningococcal serogroups ABCWY vaccine (MenABCWY) could provide broad protection against disease-causing meningococcal strains and simplify the immunisation schedule. The aim of this trial was to confirm the effect of the licensed meningococcal serogroup B (MenB) vaccine, 4CMenB, against diverse MenB strains, and to assess the breadth of immune response against a panel of 110 MenB strains for MenABCWY containing the antigenic components of 4CMenB and licensed serogroups ACWY vaccine, MenACWY-CRM, the non-inferiority of the immune response with MenABCWY versus 4CMenB and MenACWY-CRM, safety, and MenABCWY lot-to-lot consistency. METHODS: We conducted a phase 3 randomised, controlled, observer-blinded trial of healthy adolescents and young adults (age 10-25 years) across 114 centres in Australia, Canada, Czechia, Estonia, Finland, Türkiye, and the USA. Exclusion criteria included previous vaccination with a MenB vaccine or (within the last 4 years) MenACWY vaccine. Participants were randomly allocated (5:5:3:3:3:1 ratio) via a central randomisation system using a minimisation procedure to receive 4CMenB at months 0, 2, and 6 (referred to as 4CMenB 0-2-6 hereafter); or 4CMenB at months 0 and 6 (referred to as 4CMenB 0-6 hereafter); or MenABCWY (three groups, each receiving one production lot of the MenACWY-CRM component) at months 0 and 6; or MenACWY-CRM at month 0. Demonstration in the per-protocol set of the consistency of three MenACWY-CRM component lots of the MenABCWY vaccine was a primary objective (demonstrated with two-sided 95% CIs for the ratio of human serum bactericidal antibody [hSBA] geometric mean titres against each serogroup within predefined criteria [0·5-2·0]). The primary endpoints (breadth of immune response) for the MenB component of MenABCWY and 4CMenB were measured using the endogenous complement hSBA (enc-hSBA) assay against a panel of 110 diverse MenB invasive disease strains. For each serum sample, 35 strains from the 110 MenB strain panel were randomly selected for testing. The 4CMenB breadth of immune response data have been published separately. For MenABCWY, breadth of immune response was assessed in two analyses: a test-based analysis of the percentage of samples (tests) without bactericidal serum activity against MenB strains 1 month after two MenABCWY doses versus the percentage after one MenACWY-CRM dose in the per-protocol set, and a responder-based analysis of the percentage of participants (responders) whose sera killed 70% or more strains at 1 month after two MenABCWY doses in the full analysis set. A lower limit of two-sided 95% CI above 65% would demonstrate breadth of immune response. Other primary outcomes included non-inferiority (5% margin) of two MenABCWY doses versus two 4CMenB doses by enc-hSBA assay in the per-protocol set, non-inferiority (10% margin) of two MenABCWY doses versus one MenACWY-CRM dose in MenACWY vaccine-naive participants by traditional hSBA assay in the per-protocol set, and safety in all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT04502693, and is complete. FINDINGS: Between Aug 14, 2020, and Sept 3, 2021, 3651 participants were enrolled and randomly allocated (900 in the 4CMenB 0-2-6 group and 908 in the 4CMenB 0-6 group, 1666 in the three MenABCWY groups combined, and 177 in the MenACWY-CRM group). All primary objectives for MenABCWY were met. Consistency of immune responses against the three production lots of the MenACWY component of MenABCWY was demonstrated since two-sided 95% CIs for the ratios of hSBA geometric mean titres against serogroups A, C, W, and Y for each pair of lots were within the predefined equivalence criteria. The lot data were pooled for the remainder of MenABCWY endpoints. By enc-hSBA assay, breadth of immune response against the MenB strain panel was 77·9% (95% CI 76·6 to 79·2) in the test-based analysis and 84·1% (81·4 to 86·5; 687 of 817 participants) in the responder-based analysis. Non-inferiority of MenABCWY to 4CMenB was demonstrated by enc-hSBA assay: the difference in percentage of samples with bactericidal serum activity between the MenABCWY group (82·5% [95% CI 82·1 to 83·0]; 21 222 of 25 715) and 4CMenB 0-2 group (83·1% [82·7 to 83·6]; 22 921 of 27 569) was -0·61% (-1·25 to 0·03). Non-inferiority of two-dose MenABCWY to one-dose MenACWY-CRM was demonstrated by traditional hSBA assay, with differences between the MenABCWY group and MenACWY group in percentages of participants with a four-fold rise in hSBA titres of 11·3% (5·9 to 19·0) for serogroup A, 47·2% (38·1 to 56·3) for serogroup C, 35·3% (26·9 to 44·5) for serogroup W, and 27·0% (19·4 to 35·8) for serogroup Y. MenABCWY reactogenicity was mostly of mild or moderate severity and transient, with similar frequencies of adverse events in the MenABCWY and 4CMenB groups and no safety concerns were identified. INTERPRETATION: This study demonstrates breadth of immune response against a panel of 110 MenB strains for the MenB component of the investigational MenABCWY vaccine, when administered as a 0-6 months schedule to the target population of adolescents and young adults, with predefined criteria for success met for both breadth of immune response endpoints and for non-inferiority versus 4CMenB. This investigational vaccine could provide broad meningococcal serogroup coverage in a simplified immunisation schedule, thus aiding the public health attempt in preventing invasive meningococcal disease due to five Neisseria meningitidis serogroups in adolescents and young adults. FUNDING: GSK.

• MeSH
• Child MeSH
• Adult MeSH
• Immunogenicity, Vaccine * MeSH
• Single-Blind Method MeSH
• Humans MeSH
• Meningococcal Infections * prevention & control   immunology   MeSH
• Meningococcal Vaccines * immunology   adverse effects   administration & dosage   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Neisseria meningitidis, Serogroup B immunology   MeSH
• Neisseria meningitidis immunology   MeSH
• Antibodies, Bacterial blood   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Equivalence Trial MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH

BACKGROUND AND OBJECTIVES: For thousands of years, betel nut has been used as a psychoactive agent in Asian and Oceanian populations. Betel nut chewing was associated with the alteration of human oral microbiome and with diseases such as oral cancer and periodontitis, but only in populations of Asian cultural background. We studied the influence of betel nut chewing on the oral microbiome in Papua New Guinea, where half of the population uses betel nut and the prevalence of these diseases is one of the highest in the world. METHODOLOGY: We characterized the oral microbiomes of 100 Papua New Guineans. We defined two cohorts of betel chewers (n = 50) and non-chewers (n = 50) based on a genetic approach to identify the presence of betel nut in saliva. We statistically compared the alpha and beta microbial diversities between the two cohorts. We performed linear discriminant analyses to identify bacterial species more prevalent in each cohort. RESULTS: We found that oral microbial diversity is significantly different between betel chewers and non-chewers. The dysbiosis observed in betel chewers, led to an increase of pathogenic bacterial species including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, known to be in the aetiology of periodontal diseases. CONCLUSIONS AND IMPLICATIONS: Our study strongly supports the alteration of human oral microbiome by betel nut use, potentially leading to periodontal diseases. It also shows the need to consider local specificities (e.g. different habits, betel nut types, and oral microbial diversities) to better characterize the impact of betel nut chewing on health.

• Publication type
• Journal Article MeSH

One of the most common statistical analyses in experimental psychology concerns the comparison of two means using the frequentist t test. However, frequentist t tests do not quantify evidence and require various assumption tests. Recently, popularized Bayesian t tests do quantify evidence, but these were developed for scenarios where the two populations are assumed to have the same variance. As an alternative to both methods, we outline a comprehensive t test framework based on Bayesian model averaging. This new t test framework simultaneously takes into account models that assume equal and unequal variances, and models that use t-likelihoods to improve robustness to outliers. The resulting inference is based on a weighted average across the entire model ensemble, with higher weights assigned to models that predicted the observed data well. This new t test framework provides an integrated approach to assumption checks and inference by applying a series of pertinent models to the data simultaneously rather than sequentially. The integrated Bayesian model-averaged t tests achieve robustness without having to commit to a single model following a series of assumption checks. To facilitate practical applications, we provide user-friendly implementations in JASP and via the RoBTT package in R . A tutorial video is available at https://www.youtube.com/watch?v=EcuzGTIcorQ.

• MeSH
• Bayes Theorem MeSH
• Psychology, Experimental * methods   MeSH
• Data Interpretation, Statistical MeSH
• Humans MeSH
• Models, Statistical * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cancer and its treatment may lead to kidney injury and the need for kidney replacement therapy (KRT). We identified 287 pediatric KRT patients with a history of malignancy from the European Society for Paediatric Nephrology/European Renal Association Registry. Of these, 197 had cancer as a primary cause of KRT (group 1) and 90 had a malignancy diagnosis before KRT (group 2). Two matched controls without malignancy were randomly selected for each patient. Data were complemented with a questionnaire. Median time to kidney transplantation (KT) from KRT initiation was 2.4 (IQR: 1.5-4.7), 1.5 (IQR: 0.4-3.3), 3.6 (IQR: 1.3 to Q3 not reached), and 1.1 (IQR: 0.3-3.6) years for group 1, their controls, group 2, and their controls, respectively. Overall 10-year mortality for those on KRT was higher among cancer patients vs controls in group 1: 16% vs 9% (adjusted hazard ratio 2.02, 95% CI: 1.21-3.37) and in group 2: 23% vs 14% (adjusted hazard ratio 2.32, 95% CI: 1.11-4.85). In contrast, 10-year patient survival after the first KT was comparable to controls (93% vs 96%; 100% vs 94%, in groups 1 and 2, respectively). In summary, childhood cancer survivors' KT was delayed, and their overall mortality when on KRT was increased, but once transplanted, their long-term outcome was similar to other KT recipients.

• MeSH
• Kidney Failure, Chronic * mortality   etiology   therapy   MeSH
• Child MeSH
• Glomerular Filtration Rate MeSH
• Infant MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Neoplasms * complications   mortality   MeSH
• Renal Replacement Therapy * mortality   MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Graft Survival MeSH
• Prognosis MeSH
• Registries * MeSH
• Graft Rejection * mortality   etiology   MeSH
• Risk Factors MeSH
• Case-Control Studies MeSH
• Kidney Transplantation * mortality   MeSH
• Kidney Function Tests MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: In a previously published randomised, placebo-controlled trial, 800 mg/day of pharmaceutical-grade chondroitin sulfate (CS) was shown to be superior to placebo in reducing pain and improving function over 6 months in patients with symptomatic knee osteoarthritis (OA). The aim of the current post hoc analyses was to evaluate the cost-effectiveness of CS compared with placebo in a European perspective using individual patient data from this clinical trial. METHODS: Patients with knee OA randomised to CS or placebo were followed up at 1, 3 and 6 months. The algo-functional Lequesne index was used to derive the EuroQol Five-Dimension Five-Level (EQ-5D-5L) score based on a validated formula. The EQ-5D-5L scores at each time point were used to calculate the changes in quality-adjusted life years (QALYs) with the area under the curve method. Costs were assessed using the average price of CS in the countries where the original study took place and where CS is currently marketed. The costs of CS in three countries were then used (i.e. the Czech Republic, Italy and Switzerland). The incremental cost-effectiveness ratio (ICER) threshold for CS to be considered cost-effective was set at 91,870 EUR per QALY (equivalent to the usually recommended threshold of US $100,000). The study used an intention-to-treat population, i.e. patients who received one dose of the study drug, and imputed missing values using the basal observation carried forward method. RESULTS: No significant differences in baseline characteristics were observed between the CS group (N = 199) and the placebo group (N = 205). The mean cost of CS for 6 months of treatment was 194.74 EUR. After 6 months of treatment, CS showed a mean ICER of 33,462 (95% CI 5130-61,794) EUR per QALY gained, indicating cost-effectiveness compared with placebo. The acceptability curve for cost-effectiveness shows that the CS treatment is likely to be cost-effective compared with placebo, with a 93% probability when the ceiling ratio is set at 91,870 EUR per QALY gained. CONCLUSIONS: These results highlight the role of CS as a cost-effective therapeutic option in the management of OA. However, further studies taking into account the use of other healthcare resources are warranted for a more complete understanding.

• MeSH
• Cost-Effectiveness Analysis MeSH
• Cost-Benefit Analysis * MeSH
• Osteoarthritis, Knee * drug therapy   economics   MeSH
• Chondroitin Sulfates * therapeutic use   economics   MeSH
• Quality-Adjusted Life Years * MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• Czech Republic MeSH
• Italy MeSH
• Switzerland MeSH

Cervical cancer (CC) is the fourth most common malignant tumor in women worldwide. Detecting different biomarkers together on single cells by novel method mass cytometry could contribute to more precise screening. Liquid-based cytology (LBC) cervical samples were collected (N = 53) from women categorized as normal and precancerous lesions. Human papillomavirus was genotyped by polymerase chain reaction, while simultaneous examination of the expression of 29 proteins was done by mass cytometry (CyTOF). Differences in cluster abundances were assessed with Spearman's rank correlation as well as high dimensional data analysis (t-SNE, FlowSOM). Cytokeratin (ITGA6, Ck5, Ck10/13, Ck14, Ck7) expression patterns allowed determining the presence of different cells in the cervical epithelium. FlowSOM analysis enabled to phenotype cervical cells in five different metaclusters and find new markers that could be important in CC screening. The markers Ck18, Ck18, and CD63 (Metacluster 3) showed significantly increasing associated with severity of the precancerous lesions (Spearman rank correlation rho 0.304, p = 0.0271), while CD71, KLF4, LRIG1, E-cadherin, Nanog and p53 (Metacluster 1) decreased with severity of the precancerous lesions (Spearman rank correlation rho -0.401, p = 0.0029). Other metaclusters did not show significant correlation, but metacluster 2 (Ck17, MCM, MMP7, CD29, E-cadherin, Nanog, p53) showed higher abundance in low- and high-grade intraepithelial lesion cases. CyTOF appears feasible and should be considered when examining novel biomarkers on cervical LBC samples. This study enabled us to characterize different cells in the cervical epithelium and find markers and populations that could distinguish precancerous lesions.

• MeSH
• Cervix Uteri pathology   metabolism   MeSH
• Adult MeSH
• Uterine Cervical Dysplasia diagnosis   pathology   MeSH
• Papillomavirus Infections pathology   diagnosis   virology   MeSH
• Kruppel-Like Factor 4 * MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Uterine Cervical Neoplasms * diagnosis   pathology   genetics   MeSH
• Precancerous Conditions * pathology   diagnosis   MeSH
• Flow Cytometry * methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH