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Background. Despite the high transmissibility of SARS-CoV-2, some individuals remain uninfected despite prolonged exposure to a high viral load, suggesting the involvement of an innate resistance mechanism, possibly underpinned by the host’s genetic factors. The angiotensin-converting enzyme-1 (ACE1), ACE2, and C-C Chemokine Receptor 5 (CCR5) polymorphisms have been shown to influence susceptibility to the infection. In this study, the role of ACE1, ACE2, and CCR5 gene polymorphisms in modulating susceptibility to SARS-CoV-2 infection within the context of intimate contact was evaluated. Methods. A cohort of heterosexual couples from Northern Sardinia, characterized by a homogenous genetic background, was recruited during the initial pandemic wave (March–June 2020). In each couple, one partner (index case) tested positive for SARS-CoV-2 by at least two consecutive independent molecular tests (real-time polymerase chain reaction: RT-PCR) on nasopharyngeal swabs. Bed-sharing partners of SARS-CoV-2 positive index cases, resistant and susceptible to the infection, were genotyped for ACE1 287 bp Alu repeat insertion/deletion (I/D) polymorphism, ACE2 G8790A (rs2285666) variant, and a 32-base pair deletion (Δ32) of CCR5. Resistant and susceptible partners to the infection were compared for polymorphisms. Results. Out of 63 couples, 30 partners acquired SARS-CoV-2 infection, while 33 remained uninfected despite intimate exposure. Clinical history was minimal for current or past illnesses. SARS-CoV-2-infected index spouses and partners who acquired the infection developed a mild disease, not requiring hospitalization. The observed distribution of ACE1 I/D and ACE2 G8790A genotypes was consistent with previously reported frequencies in Sardinia and across European populations. None of the study participants carried the CCR5-Δ32 variant. No statistically significant differences (p > 0.05) in the allelic or genotypic frequencies of these polymorphisms were observed between the infected and resistant partners. Conclusions. No differences in the distribution of ACE1, ACE2, and CCR5 polymorphisms between the two groups were detected. These findings suggest that resistance is likely multifactorial, involving a complex interplay of genetic, immunological, and environmental factors.

Helicobacter pylori infects about half of the global population and is a major cause of peptic ulcer disease and gastric cancer. Improving patient education can increase screening participation, enhance treatment adherence, and help reduce gastric cancer incidence. Recently, large language models (LLMs) such as ChatGPT, Gemini, and DeepSeek-R1 have been explored as tools for producing patient-facing educational materials; however, their performance compared to expert gastroenterologists remains under evaluation. This narrative review analyzed seven peer-reviewed studies (2024–2025) assessing LLMs’ ability to answer H. pylori-related questions or generate educational content, evaluated against physician- and patient-rated benchmarks across six domains: accuracy, completeness, readability, comprehension, safety, and user satisfaction. LLMs demonstrated high accuracy, with mean accuracies typically ranging from approximately 77% to 95% across different models and studies, and with most models achieving values above 90%, comparable to or exceeding that of general gastroenterologists and approaching senior specialist levels. However, their responses were often judged as incomplete, described as “correct but insufficient.” Readability exceeded the recommended sixth-grade level, though comprehension remained acceptable. Occasional inaccuracies in treatment advice raised safety concerns. Experts and medical trainees rated LLM outputs positively, while patients found them less clear and helpful. Overall, LLMs demonstrate strong potential to provide accurate and scalable H. pylori education for patients; however, heterogeneity between LLM versions (e.g., GPT-3.5, GPT-4, GPT-4o, and various proprietary or open-source architectures) and prompting strategies results in variable performance across studies. Enhancing completeness, simplifying language, and ensuring clinical safety are key to their effective integration into gastroenterology patient education.

Trained immunity is a concept in immunology in which innate immune cells, such as monocytes and macrophages, exhibit enhanced responsiveness and memory-like characteristics following initial contact with a pathogenic stimulus that may promote a more effective immune defense following subsequent contact with the same pathogen. Helicobacter pylori, a bacterium that colonizes the stomach lining, is etiologically associated with various gastrointestinal diseases, including gastritis, peptic ulcer, gastric adenocarcinoma, MALT lymphoma, and extra gastric disorders. It has been demonstrated that repeated exposure to H. pylori can induce trained immunity in the innate immune cells of the gastric mucosa, which become more responsive and better able to respond to subsequent H. pylori infections. However, interactions between H. pylori and trained immunity are intricate and produce both beneficial and detrimental effects. H. pylori infection is characterized histologically as the presence of both an acute and chronic inflammatory response called acute-on-chronic inflammation, or gastritis. The clinical outcomes of ongoing inflammation include intestinal metaplasia, gastric atrophy, and dysplasia. These same mechanisms may also reduce immunotolerance and trigger autoimmune pathologies in the host. This review focuses on the relationship between trained immunity and H. pylori and underscores the dynamic interplay between the immune system and the pathogen in the context of gastric colonization and inflammation.

Background: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. Methods: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. Results: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not. Conclusion: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.

Probiotics demonstrated to be effective in the treatment of inflammatory bowel disease (IBD). However, the safety profile of probiotics is insufficiently explored. In the present systematic review and meta-analysis, we examined the occurrence of side effects related to probiotic/synbiotic use in randomized controlled trials (RCTs) of IBD patients as compared with placebo. Eligible RCTs in adult patients with IBD were identified by accessing the Medline database via PubMed, EMBASE, CENTRAL and the Cochrane central register of controlled trials up to December 2018. Occurrence of side effects was retrieved and recorded. Data were pooled and the relative risks (RRs) with their 95% confidence intervals (CIs) were calculated. The low-moderate study heterogeneity, assessed by the I2 statistic, allowed to use of a fixed-effects modelling for meta-analysis. Nine RCTs among 2337, including 826 patients (442 treated with probiotics/symbiotic and 384 with placebo) were analyzed. Eight were double-blind RCTs, and six enrolled ulcerative colitis (UC) patients. Although the risk for the overall side effects (RR 1.35, 95%CI 0.93–1.94; I2 = 25%) and for gastrointestinal symptoms (RR 1.78, 95%CI 0.99–3.20; I2 = 20%) was higher in IBD patients taking probiotics than in those exposed to placebo, statistical significance was achieved only for abdominal pain (RR 2.59, 95%CI 1.28–5.22; I2 = 40%). In conclusion, despite the small number of RCTs and the variety of probiotic used and schedule across studies, these findings highlight the level of research effort still required to identify the most appropriate use of probiotics in IBD.

Health and longevity in humans are influenced by numerous factors, including lifestyle and nutrition. However, the direct relationship between lifetime eating habits and functional capacity of the elderly is poorly understood. This study investigated the dietary changes across nutrition transition (NT) in the early 1960s, in a population located in the Sardinia island known for its longevity, dubbed as “Longevity Blue Zone” (LBZ), as well as the relationship between the dietary patterns and a panel of health indicators. A total of 150 oldest-old participants (89 women and 61 men, age range 90–101 years) living in the LBZ were recruited. Participants were interviewed using validated questionnaires to assess the consumption frequency of common food items, as well as the correlation with self-rated health, comorbidity, affective and cognitive level, physical mobility, disability and anthropometric parameters. Differences between subgroups were evaluated using the Mann-Whitney U test for independent samples or the Wilcoxon signed-rank test for paired samples. Correlation analysis was performed by calculating the Spearman correlation coefficient, separately in males and females. Compared to the pre-NT epoch, the consumption of meat, olive oil and fresh fruit slightly increased, while the consumption of lard, legumes and vegetables decreased. A significant association was found between increased olive oil intake across NT and self-rated health (ρ = 0.519), mobility (ρ = 0.502), improved vision (ρ = −0.227) and hearing (ρ = −0.314); increased chicken meat intake and performance in activities of daily living (basic activities of daily living: ρ = 0.351; instrumental activities of daily living: ρ = 0.333). Instead, vegetable consumption showed low correlation with health indicators. A mild increase in meat intake, mostly pastured poultry, is associated with better physical performance in the Sardinian LBZ elders, suggesting that a supply of protein may have been crucial to maintaining adequate functional capacity.

More than two decades ago, in the central-eastern region of the Mediterranean island of Sardinia, a mountain area was identified where the population displays exceptional longevity, especially among men (the Longevity Blue Zone, LBZ). This community was thoroughly investigated to understand the underlying causes of the phenomenon. The present study analyzed 11 genetic markers previously associated with increased survival in several long-lived populations. APOE (rs429358 and rs7412), APOE promoter (rs449647, rs769446, and rs405509), ACE1 (rs1799752), IL6 ‒174G/C (rs1800795), TNFα ‒308G/A (rs1800629), FOXO3A (rs2802292), KLOTHO (rs9536314) and G6PD (rs5030868) polymorphisms were investigated. PCR-based genotyping was performed following genomic DNA extraction from 150 nonagenarians living in the LBZ and 150 controls from a nearby area. No significant deviation in the frequency of the analyzed markers was detected between the two subgroups except for a weak association with the − 174G > C gene variant in the IL-6 gene ( p  = 0.040), which codes for a major modulator of the inflammatory response. Overall, the findings of this study do not support a significant association of known genetic variants on survival in the population of the Sardinian LBZ, suggesting that other genetic or epigenetic traits not yet identified might play a role.

First of all, the short follow-up period (2 years) presumably implied less intense temporal variations in the measurements carried out, to such an extent that some results were not statistically significant (e.g. stride length); this might be attributed to the short observation time rather than to a true lack of association. [...]since among the exclusion criteria of the participants there was the use of ambulatory devices, it cannot be ruled out that the study participants displayed an overall better performance than their aged peers in the sampled population, which may potentially limit, albeit mildly, the generalizability of the results. [...]a concern remains about reverse causation, widely discussed in the literature (Gow et al., 2012), namely whether it is the better physical activity of Blue Zoners that causes an improvement in mental performance, or whether, on the contrary, individuals with a higher level of psychological well-being can manage to engage in more effective and longer lasting motor activities.

Background/Objectives: Hypercholesterolemia is commonly viewed as a risk factor for coronary heart disease; however, several studies have reported an inverse relationship between cholesterol levels and cardiovascular mortality, particularly in older adults. This “cholesterol paradox” challenges the conventional understanding of lipid metabolism. Despite often being dismissed as a result of reverse causality, the precise causes of this paradox remain poorly understood. This study aimed to investigate the potential existence of the cholesterol paradox in a long-lived population from central Sardinia, Italy. Methods: We recruited 168 baseline nonagenarians (81 males, 87 females) from the longevity Blue Zone area in 2018 and followed them until December 2024. The lipid profile was determined for all participants according to current guidelines, and its impact on survival was analyzed with Kaplan–Meier curves and Cox proportional hazards regression models. Results: The median total cholesterol was 199.5 (range 89–314) mg/dL in males and 202.5 (range 89–324) mg/dL in females. Survival time was significantly longer in participants with LDL cholesterol (LDL-C) above 130 mg/dL compared to that in nonagenarians with LDL-C lower than 130 mg/dL (3.82 ± 1.88 years vs. 2.79 ± 1.56 years, p < 0.0001). Cox regression analysis revealed a significant reduction in the hazard ratio (HR) for mortality in participants with mild hypercholesterolemia (LDL-C ≥ 130 mg/dL) compared to that in those with normal cholesterol (OR 0.600, 95%CI 0.405–0.891). Conclusions: In the long-lived population examined, the cholesterol paradox was unlikely to be a reflection of reverse causality. Our results challenge the common view that longevity is invariably associated with low cholesterol levels. Furthermore, moderate hypercholesterolemia does not preclude the oldest adult from attaining advanced ages, contrary to common belief.

Background: The risk of developing thyroid disorders (TDs) in subjects with inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. The aim of this study was to explore the association between autoimmune (AITD) and G6PD deficiency in Northern Sardinia, in a population with a high frequency of these two conditions. Methods: In this retrospective single-center case–control study, demographic and clinical data were collected from patients examined in a tertiary referral Gastroenterology Section of a teaching hospital. Results: In 8894 subjects examined (64.7% females), 1218 patients were diagnosed with TDs; more specifically, 767 were diagnosed with AITD and 451 were not (non-AITD). Overall, G6PD deficiency was more prevalent in TD patients compared with patients without TD (controls) (16.7% vs. 11.2%; p < 0.0001). Multivariable logistic regression analysis (after adjusting for age, sex, excess weight and smoking habits), confirmed a higher risk of AITD among G6PD deficient patients with an odds ratio (OR) of 1.36 and 95% confidence interval (CI) of 1.11–1.6, female patients (OR 1.33, 95% CI 1.07–1.65) and overweight patients (OR 1.22, 95% CI 1.03–1.44). Conclusions: The risk of AITD is increased in carriers of G6PD deficiency. A careful assessment of thyroid function is advisable in patients with inherited G6PD defects.