Multiple Sclerosis (MS) exhibits considerable heterogeneity in phenotypic expression, course, prognosis and response to therapy. This suggests this disease involves multiple, as yet poorly understood, causal mechanisms. In this work we assessed the possible causal link between gene expression level of five selected genes related to the pro-inflammatory NF-κB signaling pathway (i.e., CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10) in ten different brain tissues (i.e., cerebellum, frontal cortex, hippocampus, medulla, occipital cortex, putamen, substantia nigra, thalamus, temporal cortex and intralobular white matter) and MS. We adopted a two-stage Mendelian Randomization (MR) approach for the estimation of the causal effects of interest, based on summary-level data from 20 multiplex Sardinian families and data provided by the United Kingdom Brain Expression Consortium (UKBEC). Through Radial-MR and Cochrane’s Q statistics we identified and removed genetic variants which are most likely to be invalid instruments. To estimate the total causal effect, univariable MR was carried out separately for each gene and brain region. We used Inverse-Variance Weighted estimator (IVW) as main analysis and MR-Egger Regression estimator (MR-ER) and Weighted Median Estimator (WME) as sensitivity analysis. As these genes belong to the same pathway and thus they can be closely related, we also estimated their direct causal effects by applying IVW and MR-ER within a multivariable MR (MVMR) approach using set of genetic instruments specific and common (composite) to each multiple exposures represented by the expression of the candidate genes. Univariate MR analysis showed a significant positive total causal effect for CCL2 and NFKB1 respectively in medulla and cerebellum. MVMR showed a direct positive causal effect for NFKB1 and TNFRSF1A, and a direct negative causal effect for CCL2 in cerebellum; while in medulla we observed a direct positive causal effect for CCL2. Since in general we observed a different magnitude for the gene specific causal effect we hypothesize that in cerebellum and medulla the effect of each gene expression is direct but also mediated by the others. These results confirm the importance of the involvement of NF-κB signaling pathway in brain tissue for the development of the disease and improve our understanding in the pathogenesis of MS.

Background: Epstein–Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that HLA‐E*01:03, in contrast to HLA‐E*01:01, may protect against MS through more effective immune responses against EBV‐infected B cells. However, the role of HLA‐E*01 in MS remains unclear.Methods: We investigated if HLA‐E*01:01 was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between HLA‐E*01:01 and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS‐related HLA alleles (e.g., HLA‐DRB1*15:01).Results: HLA‐E*01:01 allele alone was not significantly associated with IM or MS (p > 0.05). However, a significant interaction between HLA‐E*01:01 and IM history was observed in relation to MS risk (p < 0.001). Specifically, MS risk was significantly higher in both HLA‐E*01:01 heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], p < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], p < 0.001) with IM history, compared to HLA‐E*01:03 homozygotes. Conversely, these associations were non‐significant in individuals without IM history (p > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in HLA‐E*01:01 heterozygotes and 65% in HLA‐E*01:01 homozygotes.Conclusions: HLA‐E*01:01 carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS‐related HLA alleles. This supports the hypothesis that HLA‐E*01:01 may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating HLA‐E*01:01 into existing MHC‐based MS risk models could then enhance personalized risk assessments in individuals with IM history.

We used publicly available population data from 1 January 2019 up to 31 December 2022, to investigate mortality trends in Italy during the COVID-19 pandemic, evaluating changes in life expectancy (LE) at birth within provinces and the impact of COVID-19 vaccinations. Aggregate data analysis. Annual period life tables were used to estimate sex-specific LEs within provinces from 2019 to 2022. We used Arriaga decomposition to analyze the contribution of age groups (<60 years and ≥60 years) to annual LE changes. We implemented a Quasi-Poisson regression model to estimate the number of averted deaths by the achieved COVID-19 vaccination rates from January 2021 up to December 2022, simulating a counterfactual scenario where vaccine doses were not administered. The results revealed geographical heterogeneity in annual LE changes across Italian provinces during the pandemic. By the end of 2022, LE was below the prepandemic levels in 88% of provinces for females and in 76% for males. In addition, we estimated that the achieved vaccination rates averted 460,831 deaths (95% confidence interval: 250,976-707,920), corresponding to a 25% reduction in expected all-cause mortality. Overall, the study highlighted the significant role of COVID-19 vaccinations in averting a considerable number of deaths and improving LE. However, by the end of 2022, LE had not fully recovered to prepandemic levels in many provinces. This could be attributed to concurrent factors, including enduring COVID-19 pandemic effects, intense summer heat waves and early onset of seasonal flu. Further research and continuous monitoring are essential to fully comprehend long-term mortality trends and optimize public health strategies.

Sleep of inadequate quantity and quality is increasing in the present 24 h society, with a negative impact on physical and mental health. Mindfulness-based interventions (MBIs) generate a state of calm behavior that can reduce hyperactivity and improve sleep. We hypothesized that our specific MBI, administered online, may improve sleep quality and foster emotion regulation and mindfulness. The Pittsburgh Sleep Quality Index (PSQI), Sleep Condition Indicator (SCI), Arousal Predisposition Scale (APS), Ford Insomnia Response to Stress Test (FIRST), Sleep Hygiene Index (SHI) and Insomnia Severity Index (ISI) were used to measure sleep quality and stability. Emotion regulation and mindfulness were measured via the Emotion Regulation Questionnaire (ERQ) and Five Facet Mindfulness Questionnaire (FFMQ). Our MBI included 12 biweekly integral meditation (IM) classes, recorded IM training for individual practice, and dietary advice to promote sleep regulation. Fifty-six voluntary poor sleepers with a PSQI score of >5 were randomly allocated to treated (n = 28) and control (n = 28) groups. Linear mixed models were used to estimate the effectiveness of the intervention. Statistically significant results were observed in the FFMQ sub-domain non-reactivity to inner experience (β = 0.29 [0.06; −0.52], p = 0.01), PSQI (β = −1.93 [−3.43; −0.43], p = 0.01), SCI (β = 3.39 [0.66; 6.13], p = 0.02) and ISI (β = −3.50 [−5.86; −1.14], p = 0.004). These results confirm our hypothesis regarding the beneficial effects of our intervention on sleep quality.

Background: Previous research examining the effects of omnivorous and plant-based diets on cardiovascular disease (CVD) outcomes has produced inconsistent findings, and the importance of diet quality is overlooked. Our study aimed to develop a novel heart-protective diet index to assess the association of a high-quality, predominantly plant-based diet—including fish, eggs, and low-fat dairy products—with CVD incidence and mortality. Methods: This study included 192,274 participants in the UK Biobank (mean age: 56.3 ± 7.9 years) without CVD at baseline who completed a 24 h recall Oxford WebQ questionnaire. Using the Oxford WebQ questionnaire, we developed and validated a novel heart-protective diet score (HPDS) based on 22 food groups. Cox proportional hazard models were used to study the associations between HPDS and outcomes. Results: During a median follow-up of 12.3 years, 20,692 CVD events and 1131 CVD deaths were observed. After adjusting for demographics, Townsend deprivation index, lifestyle, and history of chronic diseases, participants in the top HPDS quartile were at lower risk, compared to those in the bottom quartile, of overall CVD (HR: 0.92 [95%CI: 0.88, 0.95]), IHD (HR: 0.89 [95%CI: 0.84, 0.94]), MI (HR: 0.85 [95%CI: 0.77, 0.94]), and HF (HR: 0.86 [95%CI: 0.77, 0.95]). Conclusions: Adherence to a healthy, predominantly plant-based heart-protective diet rich in non-starchy vegetables, fruits, wholegrains, fish, eggs, and low-fat dairy products is associated with a reduced cardiovascular disease incidence and mortality. Further research in diverse ethnic populations is necessary to examine the reproducibility of our findings and enhance generalizability.

Background: Previous investigations into multiple sclerosis (MS) risk factors predominantly relied on retrospective studies, which do not consider different follow-up times and assume a constant risk effect throughout lifetime. Objective: We aimed to evaluate the impact of genetic and early life factors on MS diagnosis by employing a time-to-event analysis in a prospective cohort. Methods: We used the UK Biobank data, considering the observation period from birth up to 31 December 2022. We considered genetic risk, using a multiple sclerosis polygenic risk score (MS-PRS), and various early life factors. Tobacco smoking and infectious mononucleosis diagnosis were also considered as time-varying variables along the follow-up. Using a Cox proportional hazards model, we examined the associations between these factors and MS diagnosis instantaneous risk. Results: We analyzed 345,027 participants, of which 1669 had an MS diagnosis. Our analysis revealed age-dependent effects for sex (females vs males) and higher MS-PRS, with greater hazard ratios observed in young adults. Conclusion: The age-dependent effects suggest that retrospective studies could have underestimated sex and genetic variants’ risk roles during younger ages. Therefore, we emphasize the importance of a time-to-event approach using longitudinal data to better characterize age-dependent risk effects.