Synthesis of Photoluminescent 2D Self-Assembled Silver Thiolate Nanoclusters for Sensors and Biomolecule Support.

Silver thiolate nanoclusters (Ag NCs) show distinctive optical properties resulting from their hybrid nature, metallic and molecular, exhibiting size-, structure-, and surface-dependent photoluminescence, thus enabling the exploitation of Ag NCs for potential applications in nanobiotechnology, catalysis, and biomedicine. However, tailoring Ag NCs for specific applications requires achieving long-term stability and may involve modifying surface chemistry, fine-tuning ligand composition, or adding functional groups. In this study, we report the synthesis of novel Ag NCs using 2-ethanephenylthiolate (SR) as a ligand, highlight critical points addressing stability, and characterize their optical and structural properties. A preliminary electrical characterization revealed high anisotropy, well suited for potential use in electronics/sensing applications. We also present the synthesis and characterization of Ag NCs using 10-carboxylic 2-ol thiolate (SR'COOH) having a terminal carboxylic group for conjugation with amine-containing molecules. We present a preliminary assessment of its bioconjugation capability using bovine serum albumin as a model protein indicating its prospective application as a biomolecule support.

Secretory immunoglobulin A in preterm infants: determination of normal values in breast milk and stool.

BACKGROUND: IgA and its secretory form sIgA impact protection from infection and necrotising enterocolitis but little is known about quantities in preterm mums own milk (MOM) or infant stool, onset of endogenous production in the preterm gut, and what affects these. METHODS: We measured by ELISA in MOM and stool from healthy preterm infants total IgA and sIgA longitudinally and additionally in MOM fresh, refrigerated, frozen, and after traversing feeding systems. RESULTS: In 42 MOM (median gestation 26 weeks), we showed total IgA levels and sIgA were highest in colostrum, fell over 3 weeks, and were not impacted by gestation. Median IgA values matched previous term studies (700 mcg/ml). In MOM recipients stool IgA was detected in the first week, at around 30% of MOM quantities. Formula fed infants did not have detectable stool IgA until the third week. Levels of IgA and sIgA were approximately halved by handling processes. CONCLUSIONS: MOM in the 3 weeks after preterm delivery contains the highest concentrations of IgA and sIgA. Endogenous production after preterm birth occurs from the 3 week meaning preterm infants are dependent on MOM for IgA which should be optimised. Routine NICU practices halve the amount available to the infant. IMPACT: (Secretory) Immunoglobulin A (IgA) is present in colostrum of maternal milk from infants as preterm as 23-24 weeks gestational age, falling over the first 3 weeks to steady levels similar to term. Gestation at birth does not impact (secretory) IgA levels in breast milk. IgA is present in very preterm infant stools from maternal milk fed infants from the first week of life, but not in formula milk fed preterm infants until week three, suggesting endogenous production from this point. Refrigeration, freezing, and feeding via plastic tubing approximately halved the amount of IgA available.

Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis.

OBJECTIVE: Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother's own breast milk (MOM) is protective, possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC. DESIGN: We performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644). RESULTS: Concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of Bifidobacterium longum and higher relative abundance of Enterobacter cloacae in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC. CONCLUSION: These results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.

Use of omic technologies in early life gastrointestinal health and disease: from bench to bedside.

Introduction: At birth, the gastrointestinal (GI) tract is colonized by a complex community of microorganisms, forming the basis of the gut microbiome. The gut microbiome plays a fundamental role in host health, disorders of which can lead to an array of GI diseases, both short and long term. Pediatric GI diseases are responsible for significant morbidity and mortality, but many remain poorly understood. Recent advancements in high-throughput technologies have enabled deeper profiling of GI morbidities. Technologies, such as metagenomics, transcriptomics, proteomics and metabolomics, have already been used to identify associations with specific pathologies, and highlight an exciting area of research. However, since these diseases are often complex and multifactorial by nature, reliance on a single experimental approach may not capture the true biological complexity. Therefore, multi-omics aims to integrate singular omic data to further enhance our understanding of disease.Areas covered: This review will discuss and provide an overview of the main omic technologies that are used to study complex GI pathologies in early life.Expert opinion: Multi-omic technologies can help to unravel the complexities of several diseases during early life, aiding in biomarker discovery and enabling the development of novel therapeutics and augment predictive models.

Outcomes of manual versus remote magnetic navigation for catheter ablation of ventricular tachycardia: a systematic review and updated meta-analysis.

PURPOSE: Ventricular tachycardia (VT) ablation is a complex procedure that requires remarkable catheter manipulation skill, great mapping accuracy and catheter stability, and can expose patients to serious complications. Magnetic navigation system (RMN)-guided ablation and contact force-sensing (CFS) catheters have the potential to overcome these obstacles. We performed a systematic review and updated meta-analysis of all available studies evaluating the outcomes of VT ablation by using RMN-guided compared to manual navigation (MAN)-guided, with and without CFS catheters. METHODS: MEDLINE/PubMed, Cochrane, and Google Scholar were searched for randomized controlled trials (RCT) or observational studies with multivariate adjustment comparing RMN-guided versus MAN-guided VT ablation. RESULTS: Thirteen studies enrolling 1348 patients (656 RMN-guided vs. 692 MAN-guided) were included. CFS catheter were used in 14% of MAN-guided patients. In comparison to MAN-guided and CFS-guided, RMN-guided VT ablation was associated with a significant higher acute ablation success (OR 2.32, 1.66-3.23 and OR 2.91, 1.29-6.53, respectively) but similar results in term of long-term VT recurrence (OR 0.75, 0.56-1.01 and OR 0.79, 0.27-2.36, respectively). RMN-guided showed a better safety profile (for all complications, OR 0.52, 0.34-0.81) and allowed a significant x-ray reduction compared to MAN-guided (OR 0.21, 0.14-0.32) and CFS-guided VT ablation (OR 0.23, 0.11-0.52, all 95% CI). CONCLUSIONS: RMN-guided was superior to MAN-guided and CFS-guided VT ablation in term of acute ablation success, all complications endpoint, and reduction of fluoroscopy exposure, but did not reduce long-term VT recurrence. Large prospective multicenter randomized trials are needed to confirm these findings.

Atrial Conduction Velocity Correlates with Frequency Content of Bipolar Signal.

BACKGROUND: Anisotropy in conduction velocity (CV) is a key substrate abnormality influencing atrial arrhythmias. In skeletal muscle fibers, CV and frequency content of the surface electromyogram signal are directly related. We hypothesized that in human atria the frequency content of the bipolar signal, recorded on the endocardial surface, is directly related to the local CV. METHODS: In 15 patients submitted to ablation of supraventricular arrhythmias, incremental pacing was performed through an octapolar catheter inserted into the coronary sinus (CS), alternatively from both extremities in two different sequences: CS bipole 1-2 as the pacing site and CS bipole 7-8 as the detection site in the first, and vice versa in the second. The pacing cycle length (PCL) was stepwise decreased from 600 ms to 500 ms, 400 ms, 300 ms, until 250 ms. Estimation of the CV was performed as the ratio between the distance traveled by the propagating pulse and the propagation time. The frequency distribution of the signal energy was estimated using the fast Fourier transform, and the characteristic frequency (CF) was estimated as the barycenter of the frequency spectrum. RESULTS: A total of 2,496 bipolar signals were analyzed; CV and CF were estimated and compared. The single patient and group data analysis showed a significant direct correlation between CV and CF of the local bipolar signal. CONCLUSIONS: Comparing the degree of spectral compression among signals registered in different points of the endocardial cardiac surface in response to decreasing PCL enables to map local differences in CV, a useful arrhythmogenic substrate index.

Role of breastfeeding in disease prevention.

Human milk provides the infant with many bioactive factors, including immunomodulating components, antimicrobials and prebiotics, which modulate the infant microbiome and immune system maturation. As a result, breastfeeding can impact infant health from infancy, through adolescence, and into adulthood. From protecting the infant from infections, to reducing the risk of obesity, type 1 diabetes and childhood leukaemia, many positive health outcomes are observed in infants receiving breastmilk. For the mother, breastfeeding protects against postpartum bleeding and depression, increases weight loss, and long-term lowers the risk of type 2 diabetes, breast and ovarian cancer, and cardiovascular diseases. Beyond infants and mothers, the wider society is also impacted because of avoidable costs relating to morbidity and mortality derived from a lack of human milk exposure. In this review, Medline was used to search for relevant articles to discuss the health benefits of breastfeeding and its societal impact before exploring future recommendations to enhance our understanding of the mechanisms behind breastfeeding's positive effects and promote breastfeeding on a global scale.

Safety and efficacy of catheter ablation for ventricular tachycardia in elderly patients with structural heart disease: a systematic review and meta-analysis.

PURPOSE: Data regarding the age-specific outcomes of VT ablation in patients with structural heart disease (SHD) are scarce. We performed a systematic review and meta-analysis to evaluate the outcomes of VT ablation in elderly vs. younger patients with SHD. METHODS: MEDLINE/PubMed, Cochrane, and Google Scholar and references comparing VT ablation in elderly vs. younger patients were screened and studies included if matching inclusion and exclusion criteria. RESULTS: Five retrospective studies enrolling 2778 SHD patients (868 elderly vs. 1910 younger) were included. Compared to younger subjects, the elderly showed similar results in terms of acute ablation success (OR 0.78, 95% CI 0.54-1.13, p = 0.189) and minor complications (OR 1.74, 95% CI 0.74-4.09, p = 0.205), a trend toward a higher risk of major complications (OR 2.30, 95% CI 0.83-6.40, p = 0.110) and significantly higher rates of all complications (OR 2.67, 95% CI 1.51-4.71, p = 0.001) and periprocedural mortality (OR 1.93, 95% CI 1.24-3.01, p = 0.004). At a mean follow-up of 18 months, elderly patients showed similar long-term VT recurrence rate (OR 1.02, 95% CI 0.85-1.22, p = 0.861) and higher all-cause mortality (OR 2.00, 95% CI 1.40-2.86, p < 0.001). In elderly patients, urgent VT ablation is associated with higher risk of major complications (beta = 0.06, p < 0.001) and periprocedural mortality (beta = 0.03, p = 0.029), while advanced age is associated with higher risk of major complications (beta = 0.29 with p = 0.009) and all complications + periprocedural mortality (beta = 0.17 with p = 0.037). CONCLUSIONS: Compared to younger patients, VT ablation in elderly showed similar results in terms of acute ablation success and long-term VT recurrence rate with a significantly higher risk of all complications, periprocedural mortality, and long-term mortality, especially when the procedure is performed urgently and in the most aged patients. Large prospective multicenter randomized trials are required to confirm these findings.

Effect of an Exclusive Human Milk Diet on the Gut Microbiome in Preterm Infants: A Randomized Clinical Trial.

Importance: The effect of using an exclusive human milk diet compared with one that uses bovine products in preterm infants is uncertain, but some studies demonstrate lower rates of key neonatal morbidities. A potential mediating pathway is the gut microbiome. Objective: To determine the effect of an exclusive human milk diet on gut bacterial richness, diversity, and proportions of specific taxa in preterm infants from enrollment to 34 weeks' postmenstrual age. Design, Setting, and Participants: In this randomized clinical trial conducted at 4 neonatal intensive care units in the United Kingdom from 2017 to 2020, microbiome analyses were blind to group. Infants less than 30 weeks' gestation who had only received own mother's milk were recruited before 72 hours of age. Statistical analysis was performed from July 2019 to September 2021. Interventions: Exclusive human milk diet using pasteurized human milk for any shortfall in mother's own milk supply and human milk-derived fortifiers (intervention) compared with bovine formula and bovine-derived fortifier (control) until 34 weeks' postmenstrual age. Fortifier commenced less than 48 hours of tolerating 150 mL/kg per day. Main Outcomes and Measures: Gut microbiome profile including alpha and beta diversity, and presence of specific bacterial taxa. Results: Of 126 preterm infants enrolled in the study, 63 were randomized to control (median [IQR] gestation: 27.0 weeks [26.0-28.1 weeks]; median [IQR] birthweight: 910 g [704-1054 g]; 32 [51%] male) and 63 were randomized to intervention (median [IQR] gestation: 27.1 weeks [25.7-28.1 weeks]; median [IQR] birthweight: 930 g [733-1095 g]; 38 [60%] male); 472 stool samples from 116 infants were analyzed. There were no differences in bacterial richness or Shannon diversity over time, or at 34 weeks between trial groups. The exclusive human milk diet group had reduced relative abundance of Lactobacillus after adjustment for confounders (coefficient estimate, 0.056; P = .03), but not after false discovery rate adjustment. There were no differences in time to full feeds, necrotizing enterocolitis, or other key neonatal morbidities. Conclusions and Relevance: In this randomized clinical trial in preterm infants using human milk-derived formula and/or fortifier to enable an exclusive human milk diet, there were no effects on overall measures of gut bacterial diversity but there were effects on specific bacterial taxa previously associated with human milk receipt. These findings suggest that the clinical impact of human milk-derived products is not modulated via microbiomic mechanisms. Trial Registration: ISRCTN trial registry identifier: ISRCTN16799022.

Untangling human milk oligosaccharides and infant gut microbiome.

The developing gut microbiome in infancy plays a key role in shaping the host immune system and metabolic state, and human milk is the main factor influencing its composition. Human milk does not only serve to feed the baby, but also to help the new-born adapt to its new environment and microbial exposures. Human milk protects the infant by providing multiple bioactive molecules, including human milk oligosaccharides (HMOs), which are the third most abundant solid component after lipids and lactose. The infant is unable to digest HMOs, so they reach the small and large intestines intact where they have many roles, including acting as prebiotics. Bifidobacterium spp. are the main, but not the only, commensals equipped with genes for HMO degradation. In this review we will outline the HMOs structures and functions, list the genes needed for their digestion, and describe the main strategies adopted by bacteria for their utilization.

Strain-specific impacts of probiotics are a significant driver of gut microbiome development in very preterm infants.

The development of the gut microbiome from birth plays important roles in short- and long-term health, but factors influencing preterm gut microbiome development are poorly understood. In the present study, we use metagenomic sequencing to analyse 1,431 longitudinal stool samples from 123 very preterm infants (<32 weeks' gestation) who did not develop intestinal disease or sepsis over a study period of 10 years. During the study period, one cohort had no probiotic exposure whereas two cohorts were given different probiotic products: Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) or Labinic (B. bifidum, B. longum subsp. infantis and L. acidophilus). Mothers' own milk, breast milk fortifier, antibiotics and probiotics were significantly associated with the gut microbiome, with probiotics being the most significant factor. Probiotics drove microbiome transition into different preterm gut community types (PGCTs), each enriched in a different Bifidobacterium sp. and significantly associated with increased postnatal age. Functional analyses identified stool metabolites associated with PGCTs and, in preterm-derived organoids, sterile faecal supernatants impacted intestinal, organoid monolayer, gene expression in a PGCT-specific manner. The present study identifies specific influencers of gut microbiome development in very preterm infants, some of which overlap with those impacting term infants. The results highlight the importance of strain-specific differences in probiotic products and their impact on host interactions in the preterm gut.

[The importance of intensive lipid-lowering therapy after acute coronary syndrome: changing the paradigm to improve the achievement of targets]. / L'importanza di una terapia ipolipemizzante intensiva dopo sindrome coronarica acuta: cambiare il paradigma per migliorare il raggiungimento dei target.

BACKGROUND: Despite the availability of effective lipid-lowering drugs, only few high-risk patients attain their LDL cholesterol (LDL-C) guideline-recommended risk-based goal because of underprescription of combination therapy. We present an 18-month experience with variation of prescription protocols after publication of the 2019 ESC/EAS guidelines for the management of dyslipidemias. METHODS: Overall, 621 consecutive patients hospitalized for acute coronary syndrome at Mauriziano Hospital in Turin, Italy, between January 2020 and June 2021 were enrolled. Lipid-lowering therapy recommended at discharge was registered to evaluate how many patients received statin monotherapy, statin plus ezetimibe combination or triple therapy with high-intensity statin plus ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). At 6-month follow-up, the reduction in LDL-C, adverse events, compliance and cardiovascular recurrences was analyzed. RESULTS: Of 621 patients enrolled, 7 died during hospitalization. During the entire study period, 33% of patients received statin monotherapy, 50% were discharged on statin-ezetimibe combination, and PCSK9i (evolocumab) was prescribed to 17% of patients. Between April 2020 and June 2021, when new recommendations were introduced into clinical practice, 20% of patients received evolocumab, 56% combination therapy and only 24% were discharged on statin monotherapy. At the beginning of observation, evolocumab was prescribed to 3% of patients hospitalized for acute coronary syndrome, while at the end of the study period 27% of patients were discharged on PCSK9i, with an increase of the prescription rate by 759%; in the same period, prescription of statin monotherapy decreased by 75%. At 6-month follow-up, LDL-C reduction was 77% in patients treated with PCSK9i vs 48% in patients taking statin-ezetimibe combination therapy (p<0.001). All patients on evolocumab reached the guideline-directed goals and a low rate of adverse events was reported, mainly represented by local injection site reactions. Six patients experienced acute coronary syndrome recurrence; only one of them was treated with evolocumab. CONCLUSION: Prescription of intensive lipid-lowering therapy after acute coronary syndrome, eventually with introduction of PCSK9i during hospitalization or at discharge, leads to attainment of guideline-recommended goals for all patients, with a low incidence of adverse events and optimal compliance.

Critical Current and Pinning Features of a CaKFe4As4 Polycrystalline Sample.

We analyze the magnetic behavior of a CaKFe4As4 polycrystalline sample fabricated by a mechanochemically assisted synthesis route. By means of DC magnetization (M) measurements as a function of the temperature (T) and DC magnetic field (H) we study its critical parameters and pinning features. The critical temperature Tc has been evaluated by M(T) curves performed in Zero Field Cooling-Field Cooling conditions. These curves show the presence of a little magnetic background for temperatures above Tc, as also confirmed by the hysteresis loops M(H). Starting from the M(H) curves, the critical current density Jc of the sample has been calculated as a function of the field at different temperatures in the framework of the Bean critical state model. The Jc(H) values are in line with the ones reported in the literature for this typology of samples. By analyzing the temperature dependence of the critical current density Jc(T) at different magnetic fields, it has been found that the sample is characterized by a strong type pinning regime. This sample peculiarity can open perspectives for future improvement in the fabrication of this material.

Tumbling Mill Process as a Tool to Develop Core-Shell Nanoparticles for Biomedical Applications. Preliminary Analysis and Testing.

A new mechanical dry process able to develop nanoparticles coated with polymeric material is proposed. An opportunely developed pilot ball milling apparatus permitted to catch-up significant process parameters that are here reported. A proper analysis of the obtained parameters permitted to individuate optimized milling conditions and to prepare a magnetite/albumin core/shell nanocomposite, material with a potential wide spread of applications in biomedical fields. The obtained powder consists in particles having a diameter of about 45 nm and exhibits a high morphological homogeneity. The proposed method is facile, low cost, solvent free and is applicable to the development of a broad range of multifunctional composites for biomedical applications.

Risk stratification of the patients with Brugada type electrocardiogram: a community-based prospective study.

AIMS: Risk stratification of patients with Brugada electrocardiogram (ECG) is being strongly debated. Conflicting results have been suggested from international registries, which enrolled non-consecutive cases, studied with different programmed electrical stimulation (PES) protocols. The aim of this study was to prospectively evaluate the incidence of arrhythmic events and the prognostic role of clinical presentation, ECG, and of a standardized PES protocol in consecutive cases from a community-based population. METHODS AND RESULTS: A total of 166 consecutive patients (45 +/- 14 years) with Brugada ECG were enrolled. Type 1 ECG was observed spontaneously in 72 (43%) and after pharmacological testing in 94 (57%). One hundred and three (62%) were asymptomatic, 58 (35%) had syncope, and five (3%) had a prior cardiac arrest. One hundred and thirty-five (81%) underwent PES with two extra stimuli up to ventricular refractoriness and 34% had ventricular fibrillation (VF) induced. Arrhythmic events occurred in nine patients at a mean follow-up of 30 +/- 21 months (2.2 events per 100 person-year): in three (60%) patients with aborted sudden death (aSD), five (8.6%) of those with syncope, and one (1%) of the asymptomatic. The only predictors of events were a history of syncope or aSD (P = 0.02) and induction at PES (P = 0.004). CONCLUSION: Clinical presentation is the most important parameter in the risk stratification of patients with Brugada ECG. Programmed electrical stimulation seems valuable, particularly in patients with previous syncope.

The role of the preterm intestinal microbiome in sepsis and necrotising enterocolitis.

Late-onset sepsis (LOS) and necrotising enterocolitis (NEC) account for the highest number of deaths in premature infants and often cause severe morbidity in survivors. NEC is an inflammatory mediated condition, but its pathophysiology remains poorly understood. There is increasing evidence that in LOS the causative organism most often translocates from the gut. No causative microorganism has been consistently associated with either LOS or NEC, but an aberrant gut microbiome development could play a pivotal role. A low bacterial diversity and a delay in anaerobic bacteria colonization may predispose preterm infants to disease development. Conversely, a predominance of Bifidobacterium species and breast milk feeding might help to prevent disease onset. With numerous studies reporting conflicting results, further research is needed to better understand the role of microorganisms and type of feeding in the health status of preterm infants.