Gianluca Gazzaniga

Background: People living with HIV (PWH) are at increased risk for metabolic and cardiovascular diseases. However, there is no structured prevention strategy for these subjects. The triglyceride‐glucose (TyG) index has shown predictive value for Type 2 diabetes mellitus (T2DM) and cardiovascular events (CVEs) in the general population, but its utility in PWH remains unclear. Methods: We conducted a retrospective study including 477 PWH without baseline T2DM. TyG index was calculated as follows: ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. ROC analysis was used to identify the optimal TyG threshold for T2DM, and logistic regression analysis was used to evaluate the association with T2DM. The association between TyG index and CVEs was investigated using Kaplan–Meier survival analysis and Cox proportional hazards regression models. Results: 477 PWH were included. Median age was 38 years and 26% were women. During a median follow‐up of 14.2 years, 38 participants developed T2DM and 45 experienced CVEs. The TyG index demonstrated fair discrimination for incident T2DM (AUC: 0.675, 95% CI 0.591–0.759), with an optimal threshold of 4.78. Participants with TyG ≥ 4.78 had a higher risk of developing T2DM (aOR 2.86, 95% CI 1.35–6.12). PWH in the highest TyG tertile had also higher risk for CVEs compared with those in the lowest tertile (aHR 3.31, 95% CI 1.10–9.97). Conclusion: In PWH, a higher TyG index was independently associated with an increased risk of both T2DM and CVEs over long‐term follow‐up. The TyG index represents a practical, low‐cost tool for early metabolic risk stratification in this population.

Background: Linezolid standard dosing is typically applied in ICU without adjustments, even in renal impairment. This study examines serum concentration variability by renal function or CRRT administration in patients receiving 1200 mg/day of linezolid. Methods: This retrospective, single-center, non-randomized observational study was conducted at Niguarda Hospital (Milan, Italy) on data from the two-year period 2023–2024. ICU patients receiving linezolid, with a renal function determination and trough TDM performed at steady-state were included and stratified by renal function or CRRT status. Results: 54 patients were included, with 18 (33%) undergoing CRRT (CVVH). CRRT patients presented higher median linezolid concentrations (4.6 mg/L) than non-CRRT patients (3.2 mg/L), and a lower risk of underdosing (17% vs. 39%). CRRT patients showed significantly lower concentrations (4.6 mg/L vs. 10 mg/L, p = 0.007) than non-CRRT patients with renal function ≤ 30 mL/min, with fewer out-of-range levels (39% vs. 91%, p = 0.008) and overdosing (22% vs. 73%, p = 0.018). A significant inverse correlation was found between renal function and linezolid levels (Spearman’s rho = −0.61, p < 0.001), with CRRT patients exhibiting concentrations comparable to those of individuals with moderately impaired renal function. Continuous infusion resulted in significantly higher median concentrations (7.2 mg/L) than extended infusion (2.7 mg/L), with an increased risk of overdosing (47% vs. 17%; p = 0.018). Conclusions: After standard-dosing administration, linezolid levels vary widely in critically ill patients. Renal function significantly affects pharmacokinetics: severe impairment increases overdose risk, while ARC may cause underdosing. Standard-dosing appears adequate in CRRT patients, with levels similar to moderate-impairment. Continuous infusion aids target attainment in normal or ARC patients but raises overdose risk in severe impairment. TDM-based personalized dosing seems crucial to optimize therapy and reduce toxicity or failure.

Background: Data on atrial fibrillation (AF) and heart failure (HF) with preserved ejection fraction (HFpEF) are scarce. We investigated the association of HFpEF with all‐cause mortality in AF. Methods: We included 10 369 patients with AF on oral anticoagulants from the nationwide ongoing START (Survey on Anticoagulated Patients Register) registry. Patients were divided into 3 groups: (1) no HF, (2) HF with reduced EF/HF with mildly reduced EF (EF ≤50%), and HFpEF (EF >50%). Patients with HF should have had a clinical diagnosis or a history of HF hospitalization. The association between HF types and all‐cause mortality was investigated by Cox proportional hazards regression analysis to estimate hazard ratio (HR) and 95% CI for each factor. The Fine–Gray model and propensity score matching were used. Results: Mean age was 76.4±9.4 years and 45.8% were women. Overall, 2309 (22.2%) patients had HF, of whom 47.4% had HFpEF. During 720±576 days of follow‐up (20 747 patients/year), 727 deaths occurred (3.5 per 100 patient‐years). After propensity score matching, both HF with mildly reduced EF/HF with reduced EF and HFpEF were associated with all‐cause mortality (HR, 1.33; P =0.037 and HR, 1.49; P =0.004). HFpEF was associated with mortality in men (HR, 1.654; P =0.001) but not in women (HR, 1.243; P =0.175). In HFpEF, age≥75 years (HR, 2.247; P =0.003), chronic respiratory disease (HR, 2.109; P P =0.035), paroxysmal AF (HR, 0.528; P =0.012), creatinine clearanceP =0.018), direct oral anticoagulants (HR, 0.575; P =0.005), and renin‐angiotensin inhibitors (HR, 0.670; P =0.033) were associated with all‐cause mortality. Conclusions: HFpEF is frequent in patients with AF and associated with an increased mortality, especially in men. Comorbidities and treatments associated differently with mortality according to HF phenotype. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02219984.

Endoscopic investigations reveal that a significant majority of individuals taking NSAIDs exhibit acute hemorrhages and mucosal erosions within the gastroduodenal lining. Ketoprofen acid (KA) is a potent NSAID with established efficacy and cardiovascular tolerability, but its gastric tolerability is a recognized limitation. To mitigate this, ketoprofen lysine salt (KLS) was developed. This review evaluates the pharmacological advantages of KLS over KA. While both KA and KLS maintain similar potency, KLS offers distinct advantages. Firstly, KLS demonstrates superior gastrointestinal protection through enhanced antioxidant properties and upregulation of mucosal defenses, as evidenced by both in vitro and in vivo studies. Secondly, KLS exhibits significantly faster absorption, leading to a more rapid onset of analgesic effects; this is attributed to its increased solubility and faster achievement of therapeutic concentrations. In essence, KLS addresses the gastric tolerability issues of KA while providing a quicker onset of action, making it a valuable alternative for patients requiring NSAID therapy, particularly those with gastric sensitivities or in need of rapid pain relief.

Vascular aging is recognized as one of the hallmarks of atherosclerosis. Currently, a growing body of evidence suggests that there exists a mutual crosstalk between telomere dysfunction and mitochondrial dysmetabolism during the process of vascular senescence. This underscores the importance of comprehensively studying the molecular mediators involved in this complex and intricate connection. In pursuit of this goal, the “VICTORIA” protocol entails a prospective single-center cohort study aimed at recruiting patients undergoing coronary angiography at Niguarda Hospital in Italy. The primary objective is to explore potential associations between peripheral markers of cell aging (telomere length and mtDNA content), dysregulation of non-coding RNA [specifically lncRNA TERRA and mitochondrial microRNA (MitomiR)], and the varied presentations of ischemic heart disease (stable angina, unstable angina, NSTEMI, and STEMI). Furthermore, we aim to investigate whether these markers correlate with vulnerable plaque characteristics, as assessed by optical coherence tomography findings. Additionally, systemic levels of pro-inflammatory biomarkers and novel indicators of senescence will be assessed. Patients will be followed up at 1 year to monitor primary outcomes including mortality, myocardial infarction, stroke, unplanned revascularization, and rehospitalization. The anticipated findings of this study hold promise for advancing our understanding of the telomere-mitochondria crosstalk, potentially paving the way for novel treatment modalities and refined risk stratification approaches for acute coronary syndrome.

Vaccination against SARS-CoV-2 has been demonstrated to be safe during gestation. Nevertheless, there are no robust data investigating the entity of maternal antibodies’ transmission through the placenta to the newborn and the persistence of the antibodies in babies’ serum. The objective of this study is to assess the maternal antibody transmission and kinetics among newborns in the first months of life. Women having received one or two doses of anti-SARS-CoV-2 mRNA-vaccines during pregnancy at any gestational age, and their newborns, were recruited and followed-up over 9 months. Ninety-eight women and 103 babies were included. At birth, we observed a significant positive correlation between maternal and neonatal serum anti-SARS-CoV-2 antibody levels and a significant negative correlation between the time since last dose and antibody levels in mothers with two doses. Over the follow-up, the birth antibody level significantly decreased in time according to the received doses number at 3, 6, and 9 months. During the follow-up, we registered 34 dyad SARS-CoV-2 infection cases. The decreasing trend was slower in the SARS-CoV-2 infection group and among breastfed non-infected babies. Antibodies from maternal anti-SARS-CoV-2 vaccination are efficiently transferred via the placenta and potentially even through breast milk. Among newborns, antibodies show relevant durability in the first months of life.

Purpose: To perform a systematic umbrella review with meta-analysis to evaluate the certainty of evidence on mortality risk associated with digoxin use in patients with atrial fibrillation (AF) with or without heart failure (HF). Methods: We systematically searched MEDLINE, Embase, and Web of Science databases from inception to 19 October 2021. We included systematic reviews and meta-analyses of observational studies investigating digoxin effects on mortality of adult patients with AF and/or HF. The primary outcome was all-cause mortality; secondary outcome was cardiovascular mortality. Certainty of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool and the quality of systematic reviews/meta-analyses by the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) tool. Results: Eleven studies accounting for 12 meta-analyses were included with a total of 4,586,515 patients. AMSTAR2 analysis showed a high quality in 1, moderate in 5, low in 2, and critically low in 3 studies. Digoxin was associated with an increased all-cause mortality (hazard ratio [HR] 1.19, 95% confidence interval [95%CI] 1.14–1.25) with moderate certainty of evidence and with an increased cardiovascular mortality (HR 1.19, 95%CI 1.06–1.33) with moderate certainty of evidence. Subgroup analysis showed that digoxin was associated with all-cause mortality both in patients with AF alone (HR 1.23, 95%CI 1.19–1.28) and in those with AF and HF (HR 1.14, 95%CI 1.12–1.16). Conclusion: Data from this umbrella review suggests that digoxin use is associated with a moderate increased risk of all-cause and cardiovascular mortality in AF patients regardless of the presence of HF. Trial registration: This review was registered in PROSPERO (CRD42022325321).

Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. Oncological therapies have been reported to be a cause of PI as well, but their role is not clearly defined. This systematic review investigates the concurrency of PI and antitumor therapy in cancer patients, considering both solid tumors and onco-hematological ones. We performed a literature review of PubMed, Embase and the Web of Science up to September 2021 according to the PRISMA guidelines. A total of 62 papers reporting 88 different episodes were included. PI was mainly reported with targeted therapies (sunitinib and bevacizumab above all) within the first 12 weeks of treatment. This adverse event mostly occurred in the metastatic setting, but in 10 cases, it also occurred also in the neoadjuvant and adjuvant setting. PI was mostly localized in the large intestine, being fatal in 11 cases, while in the remaining cases, symptoms were usually mild, or even absent. A significant risk of PI reoccurrence after drug reintroduction was also reported (6/18 patients), with no fatal outcomes. Potential pharmacological mechanisms underlying PI pathogenesis are also discussed. In conclusion, although uncommonly, PI can occur during oncological therapies and may lead to life-threatening complications; therefore, consideration of its occurrence among other adverse events is warranted in the presence of clinical suspicion.