Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Influence of quitting smoking on diabetes-related complications: A scoping review with a systematic search strategy.

INTRODUCTION: Smoking in people with diabetes markedly elevates their risk of developing complications and increases the likelihood of cardiovascular mortality. This review is the first to specifically provide evidence-based analysis about the influence of quitting smoking on diabetes-related complications in people with type 2 diabetes. METHOD: The present review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. All human clinical studies assessing the effects of stopping smoking cessation on diabetes-related complications were included. PubMed and Embase were screened until January 2024. References of primary studies and principal peer-reviewed scientific journals in the field were manually screened. RESULTS: We identified a total of 1023 studies. Only 26 met the criteria for eligibility. In general quitting smoking is associated with decreased risks of myocardial infarction and ischemic stroke. Regarding microvascular complications, the strongest evidence for the beneficial effects of smoking cessation is observed in diabetic nephropathy. However, the relationship between smoking cessation and retinopathy, neuropathy, diabetic foot complications and diabetic-related erectile dysfunction, is poorly investigated. CONCLUSION: Quitting smoking offers significant advantages in managing diabetes-related complications, significantly lowering the risks of myocardial infarction, ischemic stroke, and diabetic nephropathy. This underscores the importance of cessation. Providing evidence-based information on the benefits of stopping smoking for people with type 2 diabetes who smoke, can bolster smoking cessation efforts in the context of diabetes management.

Behavioral Therapy for People With Diabetes Who Smoke: A Scoping Review.

BACKGROUND: Tobacco smoking exacerbates diabetes-related complications; its prevalence is notwithstanding substantial. Persons with diabetes face a number of barriers and challenges to quitting such as multiple lifestyle restrictions; tailored interventions are required for smoking cessation. OBJECTIVE: To identify research on behavioral interventions for smoking cessation in diabetes. METHODS: Studies had to be randomized controlled trials, quasiexperimental or systematic reviews. The behavioral interventions included were: the 5As, Cognitive-Behavioral Therapy, Motivational Interviewing, Contingency Management, Health Coaching and Counselling, as compared to standard care. The outcomes were self-reported and/or biochemically verified smoking cessation. CINAHL Complete, MEDLINE Complete, the Cochrane databases of systematic reviews and randomized controlled trials, PsychInfo and PubMed Central were searched until July, 2023. Keywords used included diabetes, smoking cessation and each of the behavioral interventions included. RESULTS: 1615 papers were identified. Three studies on the 5As/brief advice, 4 on Motivational Intervention and 1 on counseling were retained. The results on the 5As and Motivational Interviewing were conflicting. More intensive interventions appear to be more successful in achieving smoking cessation in smokers with diabetes. CONCLUSIONS: Future research should focus on the continued development and evaluation of structured smoking cessation interventions based on the 5As, Motivational interviewing and Cognitive Behavioral Therapy.

Early and accurate diagnosis of steatotic liver by artificial intelligence (AI)-supported ultrasonography.

OBJECTIVES: Steatotic liver disease is the most frequent chronic liver disease worldwide. Ultrasonography (US) is commonly employed for the assessment and diagnosis. Few information is available on the possible use of artificial intelligence (AI) to ameliorate the diagnostic accuracy of ultrasonography. MATERIALS AND METHODS: An AI-based algorithm was developed using a dataset of US images. We prospectively enrolled 134 patients for algorithm validation. Patients underwent abdominal US and Proton Density Fat Fraction MRI scans (MRI-PDFF), assumed as reference technique. The hepatorenal index was manually calculated (HRIM) by 4 operators. An automatic hepatorenal index (HRIA) was obtained by the algorithm. The accuracy of HRIA to discriminate steatosis grades was evaluated by ROC analysis using MRI-PDFF cut-offs. RESULTS: Overweight was 40 % of subjects (BMI 26.4 kg/cm2). The median HRIA was 1.11 (IQR 0.32) and the average of 4 manually calculated HRIM was 1.08 (IQR 0.26), with a 15 % inter-operator variability. Both HRIA (R = 0.79, P < 0.0001) and HRIM (R = 0.69, P < 0.0001) significantly correlated with liver fat percentage (MRI-PDFF). According to MRI-PDFF, 32 % of enrolled subjects had steatosis. Discrimination capacity by AUC between patient with steatosis and patient without steatosis was better for HRIA than HRIM (AUC: 0.87 vs. 0.82, respectively). ROC analysis showed an AUC = 0.98 for HRIA with 1.64 cut-off in distinguishing between mild and moderate/severe groups. CONCLUSIONS: The use of AI improves accuracy and speed of ultrasonography in the diagnosis of liver steatosis. Further studies should evaluate the routine use of this technique in the management of liver steatosis at high cardio-metabolic risk.

Gender-specific insights into the irritable bowel syndrome pathophysiology. Focus on gut dysbiosis and permeability.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder involving the brain-gut interaction. IBS is characterized by persistent abdominal pain and changes in bowel habits. IBS exerts significant impacts on quality of life and imposes huge economic costs. Global epidemiological data reveal variations in IBS prevalence, both globally and between genders, necessitating comprehensive studies to uncover potential societal and cultural influences. While the exact pathophysiology of IBS remains incompletely understood, the mechanism involves a dysregulation of the brain-gut axis, leading to disturbed intestinal motility, local inflammation, altered intestinal permeability, visceral sensitivity, and gut microbiota composition. We reviewed several gender-related pathophysiological aspects of IBS pathophysiology, by focusing on gut dysbiosis and intestinal permeability. This perspective paves the way to personalized and multidimensional clinical management of individuals with IBS.

Contrasting obesity: is something missing here?

The fight against obesity is largely based on recommendations about lifestyle and therapies to initiate weight loss and, hopefully, to achieve and maintain an ideal weight. The failure of this approach is witnessed by the steady increasing rates of obesity worldwide. Lifestyle modifications yield mild weight loss with poor results in the long-term. The pharmaceutical industry is engaged to produce the best anti-obesity drugs, and this market is projected to grow massively. Guidelines on pharmacological and surgical approach to obesity are continuously developed, taking into account that benefits are counterbalanced by high costs, are limited to the period of drug intake, and potential adverse effects are possible, such as pancreatitis, gastroparesis, and bowel obstruction. Meantime, people living with obesity might simply think that taking the "magic pill" or undergoing bariatric surgery can change their life. In the long term, this tendency might lead to scarce cost-effectiveness, increasing adverse effects and inequities in the most vulnerable age classes. Furthermore, the main actors responsible for generating an obesogenic world will continue undisturbed to produce negative effects. Obesity is not only generated from voluntary individual behaviors, and no guideline can truly counteract the detrimental effects of environmental factors driving the progressive rise of obesity globally. Unsustainable food production, packaging and marketing, environmental pollution, widely diffused endocrine disrupting chemicals, and climate change are largely neglected by health professionals and generate food insecurity and malnutrition. The complexity of obesity cannot be managed only pointing to individual responsibilities of people living with obesity. There is a missing link here, and this war cannot be won in the absence of effective primary prevention measures involving changes in food production and marketing, and decreased release of toxic chemicals into the environment.

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients.

BACKGROUND: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines. MATERIALS AND METHODS: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls. RESULTS: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls. CONCLUSION: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Gut microbes in metabolic disturbances. Promising role for therapeutic manipulations?

The prevalence of overweight, obesity, type 2 diabetes, metabolic syndrome and steatotic liver disease is rapidly increasing worldwide with a huge economic burden in terms of morbidity and mortality. Several genetic and environmental factors are involved in the onset and development of metabolic disorders and related complications. A critical role also exists for the gut microbiota, a complex polymicrobial ecology at the interface of the internal and external environment. The gut microbiota contributes to food digestion and transformation, caloric intake, and immune response of the host, keeping the homeostatic control in health. Mechanisms of disease include enhanced energy extraction from the non-digestible dietary carbohydrates, increased gut permeability and translocation of bacterial metabolites which activate a chronic low-grade systemic inflammation and insulin resistance, as precursors of tangible metabolic disorders involving glucose and lipid homeostasis. The ultimate causative role of gut microbiota in this respect remains to be elucidated, as well as the therapeutic value of manipulating the gut microbiota by diet, pre- and pro- synbiotics, or fecal microbial transplantation.

A multicenter prospective randomized controlled trial investigating the effects of combustion-free nicotine alternatives on cardiovascular risk factors and metabolic parameters in individuals with type 2 diabetes who smoke: the DiaSmokeFree study protocol.

Stopping smoking is crucial for public health and especially for individuals with diabetes. Combustion-free nicotine alternatives like e-cigarettes and heated tobacco products are increasingly being used as substitutes for conventional cigarettes, contributing to the decline in smoking prevalence. However, there is limited information about the long-term health impact of those products in patients with diabetes. This randomized controlled trial aims to investigate whether switching from conventional cigarettes to combustion-free nicotine alternatives will lead to a measurable improvement in cardiovascular risk factors and metabolic parameters over a period of 2 years in smokers with type 2 diabetes. The multicenter study will be conducted in seven sites across four countries. A total of 576 smokers with type 2 diabetes will be randomly assigned (1:2 ratio) to either standard of care with brief cessation advice (Control Arm) or combustion-free nicotine alternatives use (Intervention Arm). The primary end point is the change in the proportion of patients with metabolic syndrome between baseline and the 2-year follow-up. Additionally, the study will analyze the absolute change in the sum of the individual factors of metabolic syndrome at each study time point. Patient recruitment has started in September 2021 and enrollment is expected to be completed by December 2023. Results will be reported in 2026. This study may provide valuable insights into cardiovascular and metabolic health benefits or risks associated with using combustion-free nicotine alternatives for individuals with type 2 diabetes who are seeking alternatives to tobacco cigarette smoking. The study protocol, informed consent forms, and relevant documents were approved by seven ethical review boards. Study results will be disseminated through articles published in high-quality, peer-reviewed journals and presentations at conferences.

Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations.

About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease.

The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease.

Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.

Self-reported symptoms after COVID-19 vaccination. Distinct sex, age, and geographical outcomes in Lebanese and Italian cohorts.

Following the COVID-19 discovery in December 2019, different vaccines were authorized in 2021 in Italy and Lebanon, but side effects and the impact of sex and age remained partly explored. We designed a web-based "Google Form" questionnaire to record self-reported systemic and local side effects up to 7 days after 1st and 2nd dose of the vaccine in two distinct Italian and Lebanese cohorts. Twenty-one questions in Italian and Arabic languages explored the prevalence and severity of 13 symptoms. Results were compared with respect to living country, timing, sex, and age classes. A total of 1,975 Italian subjects (age 42.9 ± SD16.8 years; 64.5% females) and 822 Lebanese subjects (age 32.5 ± SD15.9 years; 48.8% females) joined the study. The most common symptoms in both groups were injection site pain, weakness, and headache after the 1st and 2nd doses. The rate of post-vaccinal symptoms and the severity score were significantly higher in females than in males and progressively decreased with increasing age following both doses. We find that among two populations from the Mediterranean basin, the anti-COVID-19 vaccine generates mild age and sex-dependent adverse effects, with ethnic differences and prevalent symptoms rate and severity in females.

Genetic and clinical features of familial mediterranean fever (FMF) in a homogeneous cohort of patients from South-Eastern Italy.

Familial Mediterranean Fever (FMF) is linked with the MEFV gene and is the commonest among monogenic autoinflammatory diseases, with high prevalence in the Mediterranean basin. Although the clinical presentation of FMF has a major role in diagnosis, genotype/phenotype correlations and the role of "benign" gene variants (as R202Q) appear highly variable and incompletely clear, making difficult to select the most effective strategy in the management of patients. Aim of the present study was to investigate the clinical presentation and the genetic background in a homogenous cohort of patients from Apulia (south eastern Italy). We investigated 217 patients with a clinical suspect of autoinflammatory diseases, who were characterized for the occurrence of specific symptoms and with next generation sequencing by a 4-gene panel including MEFV, MVK, NLRP3 and TNFRSF1A. A genetic change was identified in 122 (53.7%) patients, with 161 different MEFV variants recorded in 100 individuals, 10 variants in NLRP3, and 6 each in TNFRSF1A and MVK. The benign variant R202Q was largely prevalent (41.6% of all MEFV variants). When patients were selected according the number of pathogenic MEFV variants (0, 1, or 2 pathogenic variants), results failed to show significant links between the frequency of symptoms and the number of pathogenic variants. Only family history and Pras score (indicative for severity of disease) predicted the presence of pathogenic variants, as compared with carriers of variants considered of uncertain significance or benign. Fever >38 °C and arthralgias appeared more frequently in R202Q-positive patients than in non-R202Q carriers. These two subgroups showed comparable duration of fever, occurrence of myalgia, abdominal and chest pain, Pras, and IFFS scores. In conclusion, results confirm that FMF manifests in mild form in non-middle eastern patients. This possibility partly affects the reliability of clinical criteria/scores. Furthermore, the presence of the R202Q variant might not be completely neutral in selected groups of patients.

Ramadan intermittent fasting reduces visceral fat and improves gastrointestinal motility.

BACKGROUND: Ramadan is a model of intermittent fasting linked with possible beneficial effects. Scarce information, however, is available about the combined effects of Ramadan intermittent fasting (RIF) on anthropometric and metabolic indices, gastrointestinal symptoms, and motility. METHODS: In 21 healthy Muslims, we assessed the impact of RIF on caloric intake, physical activity, gastrointestinal symptoms and motility (gastric/gallbladder emptying by ultrasonography, orocaecal transit time by lactulose breath test), anthropometric indices, subcutaneous and visceral fat thickness (ultrasonography), glucose and lipid homeostasis. RESULTS: Mean caloric intake decreased from a median of 2069 kcal (range 1677-2641) before Ramadan to 1798 kcal (1289-3126) during Ramadan and increased again to 2000 kcal (1309-3485) after Ramadan. Although physical activity remained stable before, during, and after RIF, body weight, body mass index and waist circumference decreased in all subjects and in both genders, together with a significant decrease in subcutaneous and visceral fat thickness and insulin resistance. The postprandial gastric emptying speed was significantly faster after than before RIF. Fasting gallbladder volume was about 6% smaller after, than before Ramadan, with a stronger and faster postprandial gallbladder contraction. After RIF, lactulose breath test documented increased microbiota carbohydrate fermentation (postprandial H2 peak), and faster orocaecal transit time. RIF also significantly improved gastric fullness, epigastric pain and heartburn. CONCLUSIONS: RIF generates, in healthy subjects, multiple systemic beneficial effects in terms of fat burden, metabolic profile, gastrointestinal motility and symptoms. Further comprehensive studies should assess the potential beneficial effects of RIF in diseased people.

Effects of MBOAT7 polymorphism and steatosis on liver function assessed by methacetin breath test.

BACKGROUND: MBOAT7 rs641738 variant is a risk factor for nonalcoholic fatty liver disease (NAFLD) and liver fibrosis, but the relationship between this polymorphism and early liver dysfunction remains uncertain. METHODS: Eighty outpatients underwent blood analyses, liver imaging by ultrasound and acoustic radiation force impulse shear wave elastography and were genotyped for MBOAT7 (wild-type [WT], rs641738 heterozygous or homozygous) polymorphism using TaqMan assays. RESULTS: NAFLD was confirmed in 53 patients. Portal uptake and hepatocyte microsomal metabolization of (13 C)-methacetin were explored by measuring 13 CO2 appearance in exhaled air. The distribution of the MBOAT7 genotypes was comparable in subjects with or without NAFLD. The majority of subjects with or without NAFLD had fibrosis ≤ F1 but decreased portal extraction of (13 C)-methacetin, i.e. 78.6% in homozygous, 45.0% in heterozygous and 46.2% in WT for the MBOAT7 variant. Both substrate extraction and microsomal metabolization were mostly defective in the homozygous carriers. The extraction efficiency from portal blood flow was minimal in subjects with both homozygous rs641738 polymorphism and NAFLD, as compared to those with WT/heterozygous polymorphism, with or without NAFLD. CONCLUSIONS: The homozygous MBOAT7 rs641738 polymorphism per se is associated with a reduced extraction efficiency of (13 C)-methacetin from the portal flow pointing to subclinical liver dysfunction independently from liver fibrosis. Liver steatosis worsens (13 C)-methacetin extraction efficiency. We urge to better explore the mechanisms of interaction between external factors and multiple gene polymorphisms (including MBOAT7), paving the road to primary prevention and novel therapeutic strategies.

Contribution of the microbiome for better phenotyping of people living with obesity.

Obesity has reached epidemic proportion worldwide and in all ages. Available evidence points to a multifactorial pathogenesis involving gene predisposition and environmental factors. Gut microbiota plays a critical role as a major interface between external factors, i.e., diet, lifestyle, toxic chemicals, and internal mechanisms regulating energy and metabolic homeostasis, fat production and storage. A shift in microbiota composition is linked with overweight and obesity, with pathogenic mechanisms involving bacterial products and metabolites (mainly endocannabinoid-related mediators, short-chain fatty acids, bile acids, catabolites of tryptophan, lipopolysaccharides) and subsequent alterations in gut barrier, altered metabolic homeostasis, insulin resistance and chronic, low-grade inflammation. Although animal studies point to the links between an "obesogenic" microbiota and the development of different obesity phenotypes, the translational value of these results in humans is still limited by the heterogeneity among studies, the high variation of gut microbiota over time and the lack of robust longitudinal studies adequately considering inter-individual confounders. Nevertheless, available evidence underscores the existence of several genera predisposing to obesity or, conversely, to lean and metabolically health phenotype (e.g., Akkermansia muciniphila, species from genera Faecalibacterium, Alistipes, Roseburia). Further longitudinal studies using metagenomics, transcriptomics, proteomics, and metabolomics with exact characterization of confounders are needed in this field. Results must confirm that distinct genera and specific microbial-derived metabolites represent effective and precision interventions against overweight and obesity in the long-term.