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Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects. Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses. CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity. CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC.

The increasing efficacy of cancer therapies has significantly improved survival rates, but it has also highlighted the prevalence of cancer-therapy-related cardiac dysfunction (CTRCD). This review provides a comprehensive overview of the identification, monitoring, and management of CTRCD, a condition resulting from several treatments, such as anthracyclines, HER2-targeted therapies, target therapies, and radiotherapy. The paper includes a discussion of the mechanisms of CTRCD associated with various cancer treatments. Early detection through serum biomarkers and advanced imaging techniques is crucial for effective monitoring and risk stratification. Preventive strategies include pharmacological interventions such as ACE inhibitors/angiotensin receptor blockers, beta-blockers, and statins. Additionally, novel agents like sacubitril/valsartan, sodium-glucose co-transporter type 2 inhibitors, and vericiguat show promise in managing left ventricular dysfunction. Lifestyle modifications, including structured exercise programs and optimized nutritional strategies, further contribute to cardioprotection. The latest treatments for both asymptomatic and symptomatic CTRCD across its various stages are also discussed. Emerging technologies, including genomics, artificial intelligence, novel biomarkers, and gene therapy, are paving the way for personalized approaches to CTRCD prevention and treatment. These advancements hold great promise for improving long-term outcomes in cancer patients by minimizing cardiovascular complications.

BackgroundThe efficacy of intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) represents a contemporary hot topic. PCI in patients with bifurcation coronary lesions and unprotected left main lesions offers specific challenges that, theoretically, may particularly benefit from IVI.ObjectiveTo compare the clinical outcomes between IVI and angiography guidance for PCI in bifurcation and unprotected left main lesions.MethodsRandomised clinical trials (RCTs) comparing IVI (with either intravascular ultrasound or optical coherence tomography) with angiography to guide PCI in patients with bifurcation and unprotected left main lesions were searched in PubMed and Cochrane Central Register of Controlled Trials. Two investigators independently extracted study data. Risk ratios (RRs) were calculated using the random-effects model with inverse variance weighting and the 95% CIs with the modified Knapp-Hartung-Sidik-Jonkman method. The primary outcome was target vessel failure (TVF).ResultsA total of seven RCTs were included, collecting data on 2494 patients in the analysis for bifurcation lesions and 1107 patients in the analysis for unprotected left main lesions. The mean follow-up duration ranged from 12 to 36 months. Compared with angiography guidance, IVI guidance significantly reduced TVF both in bifurcation lesions (RR 0.70, 95% CI 0.53 to 0.92) and unprotected left main lesions (RR 0.55, 95% CI 0.36 to 0.84). The number needed to treat to prevent one TVF with IVI was 27 in bifurcation lesions PCI and 11 in unprotected left main PCI.ConclusionIn patients undergoing PCI on bifurcation and unprotected left main lesions, IVI guidance significantly reduces the risk of TVF compared with angiography guidance.PROSPERO registration numberCRD42024580321.

There is a real medical need of new diagnostic tools for the early recognition of invasive Candida infections. We exploited a rather simple and rapid redox methodology to construct a bispecific monoclonal antibody (bsmAb) that combines a monoclonal antibody (mAb) directed against 1,3-β-D-glucan, a well-known, pan-fungal diagnostic biomarker, with a mAb recognizing MP65, a major immunogenic mannoprotein secreted by C.albicans and other Candida species. The bsmAb (MP65/bglu mAb) was successfully produced and purified at high yields and proved to bind and reveal simultaneously, with high sensitivity, the β-glucan and MP65 antigens in both purified and native forms. The MP65/bglu mAb is the first bispecific antibody generated against a fungal microorganism and may prove useful for the concurrent detection of different and clinically significant Candida biomarkers in patient sera.

New-generation transcatheter heart valves have significantly improved technical success and procedural safety of transcatheter aortic valve implantation (TAVI) procedures; however, the incidence of permanent pacemaker implantation (PPI) remains a concern. This study aimed to assess the role of anatomic annulus features in determining periprocedural conduction disturbances leading to new PPI after TAVI using the last-generation Edwards SAPIEN balloon-expandable valves. In the context of a prospective single-center registry, we integrated the clinical and procedural predictors of PPI with anatomic data derived from multislice computed tomography. A total of 210 consecutive patients treated with balloon-expandable Edwards transcatheter heart valve were included in the study from 2015 to 2023. Technical success was achieved in 197 procedures (93.8%), and 26 patients (12.4%) required new PPI at the 30-day follow-up (median time to implantation 3 days). At the univariable logistic regression analysis, preprocedural right bundle branch block (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.01 to 4.97, p = 0.047), annulus eccentricity ≥0.25 (OR 5.43, 95% CI 2.21 to 13.36, p <0.001), calcium volume at annulus of the right coronary cusp >48 mm3 (OR 2.60, 95% CI 1.13 to 5.96, p = 0.024), and prosthesis implantation depth greater than membranous septum length (OR 2.17, 95% CI 1.10 to 4.28, p = 0.026) were associated with new PPI risk. In the multivariable analysis, preprocedural right bundle branch block (OR 2.81, 95% CI 1.01 to 7.85, p = 0.049), annulus eccentricity ≥0.25 (OR 4.14, 95% CI 1.85 to 9.27, p <0.001), and annulusright coronary cusp calcium >48 mm3 (OR 2.89, 95% CI 1.07 to 7.82, p = 0.037) were confirmed as independent predictors of new PPI. In conclusion, specific anatomic features of the aortic valve annulus might have an additive role in determining the occurrence of conduction disturbances in patients who underwent TAVI with balloon-expandable valves. This suggests the possibility to use multislice computed tomography to improve the prediction of post-TAVI new PPI risk. [Display omitted]

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNFα therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a causative role of this protein in IBD. To determine the druggability of this cytokine, we developed a novel monoclonal antibody (C269) that neutralizes in vitro the cytokine-like action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS- and dextran sulfate sodium (DSS)-induced colitis. Importantly, C269 ameliorates the symptoms by reducing pro-inflammatory cytokines. Specifically, in the lamina propria, a reduced number of inflammatory monocytes, neutrophils, Th1, and cytotoxic T lymphocytes are found upon C269 treatment. Our data demonstrate that eNAMPT participates in IBD and, more importantly, that eNAMPT-neutralizing antibodies are endowed with a therapeutic potential in IBD.Key messagesWhat are the new findings?Higher serum eNAMPT levels in IBD patients might decrease response to anti-TNF therapy.The cytokine-like activity of eNAMPT may be neutralized with a monoclonal antibody.Neutralization of eNAMPT ameliorates acute and chronic experimental colitis.Neutralization of eNAMPT limits the expression of IBD inflammatory signature.Neutralization of eNAMPT impairs immune cell infiltration in lamina propria.

Abstract Background and aims The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for the treatment of cardiogenic shock (CS) may result in left ventricle overload and distension. Percutaneous microaxial flow pump Impella in addition to VA-ECMO (ECPELLA) is an emerging option to overcome these collateral effects. Aim of this study is to assess whether the addition of Impella to VA-ECMO is an effective and safe unloading strategy. Methods and results We performed a systematic literature review of studies comparing ECPELLA vs. ECMO alone in patients with CS. The primary endpoint was early mortality (in-hospital or 30-day mortality). The secondary endpoints were bleeding, need for kidney replacement therapy, haemolysis, infections, and limb ischaemia. A total of 3469 potentially relevant articles were screened and eight retrospective studies including 11.137 patients were selected. There was no significant difference in early mortality (Risk Ratio, RR 0.90, 95% CI 0.78–1.03) between ECPELLA and ECMO. Nevertheless, there was a borderline significant reduction in early mortality with ECPELLA (RR 0.74, 95% CI 0.55–1.00) at sensitivity analysis selectively including studies reporting propensity matched analysis. ECPELLA was associated with increased bleeding (RR 1.45, 95% CI 1.20–1.75), need for kidney replacement therapy (RR 1.54, 95% CI 1.19–1.99), haemolysis (RR 1.71, 95% CI 1.41–2.07) and limb ischaemia (RR 1.43, 95% CI 1.17–1.75) and with a non-significant increase in severe infections (RR 1.26, 95% CI 0.84–1.89), compared with ECMO alone. Conclusion Among patients with cardiogenic shock, ECPELLA is associated with increased complications compared with ECMO. Whether reducing ventricular overload with Impella among patients treated with ECMO reduces early mortality needs to be confirmed by further investigations. Graphical Abstract Graphical Abstract Results of the meta-analysis for each outcome comparing ECMO plus percutaneous ventricular unloading versus ECMO alone.

BackgroundMechanisms of myocardial ischemia in obstructive and non-obstructive coronary artery disease (CAD), and the interplay between clinical, functional, biological and psycho-social features, are still far to be fully elucidated. ObjectivesTo develop a machine-learning (ML) model for the supervised prediction of obstructive versus non-obstructive CAD.MethodsFrom the EVA study, we analysed adults hospitalized for IHD undergoing conventional coronary angiography (CCA). Non-obstructive CAD was defined by a stenosis < 50% in one or more vessels. Baseline clinical and psycho-socio-cultural characteristics were used for computing a Rockwood and Mitnitski frailty index, and a gender score according to GENESIS-PRAXY methodology. Serum concentration of inflammatory cytokines was measured with a multiplex flow cytometry assay. Through an XGBoost classifier combined with an explainable artificial intelligence tool (SHAP), we identified the most influential features in discriminating obstructive versus non-obstructive CAD. ResultsAmong the overall EVA cohort (n = 509), 311 individuals (mean age 67 ± 11 years, 38% females; 67% obstructive CAD) with complete data were analysed. The ML-based model (83% accuracy and 87% precision) showed that while obstructive CAD was associated with higher frailty index, older age and a cytokine signature characterized by IL-1β, IL-12p70 and IL-33, non-obstructive CAD was associated with a higher gender score (i.e., social characteristics traditionally ascribed to women) and with a cytokine signature characterized by IL-18, IL-8, IL-23.ConclusionsIntegrating clinical, biological, and psycho-social features, we have optimized a sex- and gender-unbiased model that discriminates obstructive and non-obstructive CAD. Further mechanistic studies will shed light on the biological plausibility of these associations.Clinical trial registrationNCT02737982.

PurposeNecrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota.MethodsBroad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5–9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids.ResultsHMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth.ConclusionThis study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC.

Background: The reasons behind low adherence to the Mediterranean diet (Med-diet) are still not entirely known. We aimed to evaluate the effect of biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) factors on Med-diet adherence. Methods: Baseline Med-diet adherence was measured using a self-administered questionnaire among adults with ischemic heart disease (IHD) from the EVA (Endocrine Vascular Disease Approach) study. A multivariable analysis was performed to estimate the effect of sex- and gender-related factors (i.e., identity, roles, relations, and institutionalized gender) on low adherence. Results: Among 366 participants (66 ± 11 years, 31% women), 81 (22%) adults with low adherence demonstrated higher rates of diabetes, no smoking habit, lower male BSRI (Bem Sex Role Inventory) (median (IQR) 4.8 (4.1 to 5.5) vs. 5.1 (4.5 to 5.6) and p = 0.048), and higher Perceived Stress Scale 10 items (PSS-10) (median (IQR) 19 (11 to 23) vs. 15 (11 to 20) and p = 0.07) scores than those with medium-high adherence. In the multivariable analysis, only active smoking (odds ratio, OR = 2.10, 95% confidence interval, CI 1.14 to 3.85 and p = 0.017), PPS-10 (OR = 1.04, 95% CI 1.00 to 1.08, and p = 0.038) and male BSRI scores (OR = 0.70, 95% CI 0.52 to 0.95, and p = 0.021) were independently associated with low adherence. Conclusions: Male personality traits and perceived stress (i.e., gender identity) were associated with low Med-diet adherence regardless of the sex, age, and comorbidities. Therefore, gender-sensitive interventions should be explored to improve adherence in IHD.