Lucia La Sala

Background/Objectives: Antinuclear antibody testing by indirect immunofluorescence on HEp-2 cells (ANA-IIF) remains the reference test for systemic autoimmune rheumatic diseases (SARD). However, complete serological characterization requires integration with extractable nuclear antigen (ENA) screening, antigen-specific solid-phase assays (SPA), and confirmatory indirect immunofluorescence (IIF) tests. This study aimed to: (1) quantify real-world serological pathway incompleteness in ANA testing performed outside a structured reflex strategy; (2) compare simulated stepwise and upfront parallel reflex approaches in terms of serological yield, laboratory workload, and costs. Methods: We retrospectively analyzed 2207 consecutive patients referred for ANA-IIF testing between July 2025 and April 2026. Serological incompleteness was defined as non-completion of the predefined Regione Lombardia reflex framework. A fully characterized subgroup of 514 patients, defined by complete reflex-serological assessment, was used to compare a stepwise strategy, in which ANA-IIF positivity triggered downstream testing, with an upfront parallel strategy, in which ANA-IIF, ENA screening, and anti-double-stranded DNA (anti-dsDNA) testing were performed upfront. Results: ANA-IIF was positive in 913/2207 patients (41.4%). Overall, 508 patients (23.0%) had at least one missing follow-up assay expected under the reflex framework. In the fully characterized subgroup, the upfront parallel strategy increased the number of patients with at least one fully characterized autoantibody finding from 15 to 22 (+1.4%), but required 657 additional tests and an estimated incremental cost of approximately €2592. Conclusions: ANA-IIF testing outside a structured reflex pathway frequently resulted in incomplete serological assessment. Although the upfront parallel strategy increased serological yield, it required substantially greater laboratory workload and costs than the stepwise approach. Further studies are needed to define the optimal balance between serological yield, clinical relevance, and cost-effectiveness.

The Triglyceride-Glucose (TYG)-Index has been increasingly used as a simple surrogate marker of insulin resistance and has been associated with adverse cardiometabolic outcomes in several populations. TYG has gained great attention as a predictive index for mortality, but comparisons with other predictive indexes are unexplored, except for TYG-derived indexes such as TYG-body mass index (TYG-BMI). We conducted a comparative prognostic study in two independent cohorts of adults with obesity: a general obesity cohort (n = 1,359) and a bariatric surgery cohort (n = 854), both with long-term follow-up approaching 14 years and with different mortality rates (11.5 vs. 5.5%, respectively). We compared TYG index, TYG-BMI index, blood glucose, age, Charlson Index, metabolic syndrome, glucose tolerance, diabetes mellitus, through Cox proportional hazard models with Harrell'C index, and through ROC analysis. We also evaluated the possible incremental predictive value of the above prognostic indexes when combined with blood glucose, the TYG-index, and TYG-BMI index. Across both cohorts, several metabolic and clinical indices were significantly associated with all-cause mortality in univariable analyses. However, age and Charlson Comorbidity Index consistently showed the strongest discrimination and prognostic performance. The various indexes significantly predicted mortality at Cox proportional hazard models (p always < 0.001). Harrell'C index correlated with ROC area under the curves of each index (p < 0.001), and both Harrell and ROC correlated with quality indexes of Cox analysis (LR, p < 0.001) and with quality indexes of linear regression (F, p < 0.001). Findings were directionally consistent in the bariatric surgery cohort, although lower event rates attenuated overall discrimination. The combined use of more indices together was not uniformly useful to increase the predictive value of the above indices. In obesity, TyG-based indices are associated with long-term mortality risk but add limited prognostic value beyond age and multimorbidity burden. These markers may be considered complementary tools for metabolic characterization rather than primary instruments for mortality risk stratification. This study reinforces the concept that various mortality indexes are as valid as, or even more predictive than, TYG index.

Arterial Hypertension (AH) and Type 2 Diabetes (T2DM) are common in obesity. However, there is no data on the influence of different degrees of obesity on the frequency of the two diseases. In this cross-sectional study 3,486 patients (867 men and 2,619 women, aged 42.6 ± 11.48 years, minimum BMI 30.0 kg/m2, mean BMI 41.9 ± 6.62 kg/m2), were evaluated at presentation for bariatric surgery (BS). BMI was expressed as a continuous variable, as BMI quartiles (BMIQ), as full obesity class (I-III), as reduced obesity class (II-III), Frequency of AH and T2DM, and of a comorbidity score (CS: AH + T2DM) was recorded, and univariable and multivariable stepwise regression analysis was employed to evaluate the association of BMI indexes with AH, T2DM, and CS. AH, T2DM and CS showed increasing frequency with increasing BMI quartiles (p < 0.001), and with age (p < 0.001). AH and T2DM were frequently associated. At multivariable analysis, age and BMIQ were associated with AH (p < 0.001), T2DM (p < 0.001), and with CS (p < 0.001), more than BMI (NS for CS) full obesity class and reduced obesity class and BMI (NS for T2DM and for CS). The same results were observed at receiver operating curves (ROC), with greater area (AUC) for BMIQ than for BMI and obesity classes. The frequency of AH and T2DM increases with increasing BMI levels. BMIQ outperforms BMI and obesity classes in modelling. This finding supports the use of fine stratification of BMI in clinical risk assessment. More specific studies are required to fully understand the impact of different BMI thresholds in determining the health status of obese patients, and to reduce the risks of BS in patients with extreme obesity.

Background: Studies on morbid obese diabetic and non-diabetic patients’ social characteristics and habits, in candidates for bariatric surgery (BS) are few. To gain further insights, we investigated 799 morbid obese diabetic (n = 111) and non-diabetic patients (n = 688). Methods: Family history of cardiometabolic diseases, personal history, education and occupation, comorbidities, daily habits, previous dietetic treatment, reasons and pathway to BS were investigated. Team members involved and examinations performed were also analyzed. Results: Family histories of obesity, diabetes and hypertension significantly associated with each other, and clinically overt diseases were also associated with family histories of the same disease, as diabetes and hypertension, and were more frequent in diabetic as compared to non-diabetic (p > 0.05, p < 0.0001 and p < 0.05). Females significantly differed from males for lower body mass index (BMI) (mean 41.2 vs 42.8 kg/m ² ), and a lower alcohol intake (p < 0.05 to p < 0.001). Knowledge about BS and reasons for BS varied according to age. BS was mostly requested for medical reasons (80.1%). Conclusions: Patients seeking bariatric surgery have a valid and well structured idea of obesity and are aware of the importance of eating less and physical activity in managing obesity, with differences linked to their educational levels. The interaction between physicians and surgeons improved the overall prognosis of patients seeking BS, based on screening of CV risk factors. Improved patients long term follow-up after surgery, identification of the suitable pre-BS diets, as well and identification of patients who might benefit from non-BS approaches, such as newer medical therapies could improve long term care of obesity.

The AGE (advanced glycation end-products)–RAGE (receptor for AGE) system is a pro-inflammatory pathway that contributes to the pathogenesis of obesity and obesity-related cardiovascular disorders (CVD). Circulating AGE and the soluble form of RAGE (sRAGE) has been suggested as a potential biomarker of CVD related to obesity. In this study, we aim to (1) summarize the current knowledge about the role of obesity in the onset and progression of CVD, (2) discuss the role of the AGE–RAGE system as a pathway promoting obesity and linking obesity to CVD, and (3) highlight available strategies for reducing AGE–RAGE system activation and the associated beneficial effects.

Background/Objectives: Recent studies have highlighted the Triglyceride–Glucose Index (TYG) as a significant risk factor for mortality and co-morbidities in various populations, including those with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. However, its prognostic role in obese individuals remains less clear. Methods: Utilizing data from an obese cohort of 1359 subjects and from the 1999–2004 cycles of the National Health and Nutrition Examination Survey (NHANES) with 15,267 subjects, this study investigates the prognostic value of TYG and blood glucose in relation to age and sex and other factors such as metabolic syndrome, Charlson Comorbidity Index, T2DM and glucose tolerance, in predicting mortality among obese subjects. Over a median follow-up of about 13 years, 11.3% of the obese cohort and 20.6% of the NHANES cohort died. Our findings indicate that while TYG and blood glucose are significantly related to mortality, they offer only modest improvements over models incorporating age, sex, and other risk factors that showed a prognostic power of 76.1% and 86.0% in the respective cohorts. Conclusions: These results suggest that while TYG holds potential as a prognostic biomarker, its utility beyond established risk factors requires further validation in clinical settings.

Inflammasomes are protein complexes that trigger pro-inflammatory responses and promote many diseases, including adipose tissue dysfunction. Linagliptin (L), a DPP-4 inhibitor used for type 2 diabetes therapy, has putative anti-inflammatory effects. This work explores L effects on inflammasome regulation, inflammation, and adipose tissue dysfunction in obese mice. Male C57BL/6N mice were fed a normal chow (NC) diet, high-fat (HF) diet, or HF diet with L (HFL) for 15 weeks. Gene expression and histological examinations were performed on visceral (VAT) and subcutaneous (SAT) adipose tissue samples. Biomarkers were quantified on sera. Murine macrophages were utilized for in vitro analyses. L decreased HF-induced endotoxemia and circulating inflammatory indicators. Despite having no effect on body weight, L reduced VAT inflammation by decreasing endotoxemia-induced NLRC4 inflammasome, inflammation severity, and fat cell hypertrophy. Although SAT response differed from VAT, inflammation was slightly reduced in this tissue too. In vitro, L modulated inflammation by directly reducing the pro-inflammatory macrophage phenotype. In obesity, increased NLRC4 inflammasome expression links endotoxemia and VAT inflammation. L protected against endotoxemia, maybe by affecting gut permeability and VAT responses. The decreased polarization of macrophages toward a pro-inflammatory phenotype and the reduction in adipocyte hypertrophy are involved in the response to L.

Periodontal disease (PD) during pregnancy may trigger systemic inflammation, increasing the risk of developing cardiometabolic disease (CMD). As a consequence, PD may result in the activation of cellular and molecular pathways, affecting the disease course and pregnancy outcome. Although microRNAs (miRNAs) are considered ideal biomarkers for many diseases, few studies have investigated salivary miRNAs and their role in pregnancy or neonatal outcomes. In this study, we sought to investigate the associations between salivary miRNAs of pregnant women with oral diseases and their effects on neonatal outcomes. Eleven (n = 11) salivary miRNAs from a cohort of pregnant women with oral diseases (n = 32; oral health, H; gingivitis, G; and periodontitis, P) were detected using a previous profiling analysis with an FDR < 0.20 and a fold change (FC) < 0.5 or FC > 2 for the most highly expressed miRNAs. Spearman correlations were performed for 11 salivary microRNAs associated with oral-derived inflammation, which could affect neonatal outcomes during pregnancies at risk for cardiometabolic disease (CMD), defined by the presence of a high pregestational BMI. In addition, ROC curves demonstrated the diagnostic accuracy of the markers used. Upregulation of miR-423-5p expression and a decrease in miR-27b-3p expression were detected in the P-group (p < 0.05), and ROC analysis revealed the diagnostic accuracy of miR-423-5p for discriminating oral diseases, such as gingivitis versus periodontitis (P vs. G, AUC = 0.78, p < 0.05), and for discriminating it from the healthy oral cavity (P vs. H, AUC = 0.9, p < 0.01). In addition, miR-27b-3p and miR-622 were also able to discriminate the healthy group from the P-group (AUC = 0.8, p < 0.05; AUC = 0.8, p < 0.05). miR-483-5p was able to discriminate between the G-group (AUC = 0.9, p < 0.01) and the P-group (AUC = 0.8, p < 0.05). These data support the role of salivary miRNAs as early biomarkers for neonatal outcomes in pregnant women with periodontal disease at high risk for CMD and suggest that there is cross-talk between salivary miRNAs and subclinical systemic inflammation.