Estimation of Right Atrial Pressure by Ultrasound-Assessed Jugular Vein Distensibility in Patients With Heart Failure.

BACKGROUND: Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population. METHODS: We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup. RESULTS: A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64-0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73-0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg; P<0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank P=0.034). CONCLUSIONS: Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03874312.

The Exercise aNd hEArt transplant (ENEA) trial - a registry-based randomized controlled trial evaluating the safety and efficacy of cardiac telerehabilitation after heart transplant.

BACKGROUND: Heart transplant (HTx) is gold-standard therapy for patients with end-stage heart failure. Cardiac rehabilitation (CR) is a multidisciplinary intervention shown to improve cardiovascular prognosis and quality of life. The aim in this randomized controlled trial is to explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, biomarkers of rehabilitation outcomes will be identified, as data that will enable treatment to be tailored to patient phenotype. METHODS: Patients after HTx will be recruited at IRCCS S. Maria Nascente - Fondazione Don Gnocchi, Milan, Italy (n = 40). Consenting participants will be randomly allocated to either of two groups (1:1): an intervention group who will receive on-site CR followed by 12 weeks of telerehabilitation, or a control group who will receive on-site CR followed by standard homecare and exercise programme. Recruitment began on 20th May 2023 and is expected to continue until 20th May 2025. Socio-demographic characteristics, lifestyle, health status, cardiovascular events, cognitive function, anxiety and depression symptoms, and quality of life will be assessed, as well as exercise capacity and muscular endurance. Participants will be evaluated before the intervention, post-CR and after 6 months. In addition, analysis of circulating extracellular vesicles using Surface Plasmon Resonance imaging (SPRi), based on a rehabilomic approach, will be applied to both groups pre- and post-CR. CONCLUSION: This study will explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, a rehabilomic approach will be used to investigate biomolecular phenotypization in HTx patients. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT05824364.

Case Report: A rare homozygous patient affected by TTR systemic amyloidosis with a prominent heart involvement.

Hereditary transthyretin amyloidosis is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney, and the eyes. We present a case of a Caucasian 65-year-old man with cardiac amyloidosis and the homozygous mutation Val142Ile (classically, Val122Ile) in the transthyretin gene. We provide a genotype-phenotype correlation regarding the genetic status of both heterozygous and homozygous individuals and their clinical conditions at the time of genetic testing.

Intravenous continuous home inotropic therapy in advanced heart failure: Insights from an observational retrospective study.

INTRODUCTION: Intravenous inotropic support represents an important therapeutic option in advanced heart failure (HF) as bridge to heart transplantation, bridge to mechanical circulatory support, bridge to candidacy or as palliative therapy. Nevertheless, evidence regarding risks and benefits of its use is lacking. METHODS: we conducted a retrospective single center study, analysing the effect of inotropic therapies in an outpatient cohort, evaluating the burden of hospitalizations, the improvement in quality of life, the incidence of adverse events and the evolution of organ damage. RESULTS: twenty-seven patients with advanced HF were treated in our Day Hospital service from 2014 to 2021. Nine patients were treated as bridge to heart transplant while eighteen as palliation. Comparing data regarding the year before and after the beginning of inotropic infusion, we observed a reduction of hospitalization (46 vs 25, p<0,001), an improvement of natriuretic peptides, renal and hepatic function since the first month (p<0,001) and a better quality of life in 53% of the population treated. Two hospitalizations for arrhythmias and seven hospitalizations for catheter-related complications were registered. CONCLUSIONS: in a selected population of advanced HF patients, continuous home inotropic infusion were able to reduce hospitalizations, improving end organ damage and quality of life. We provide a practical guidance on starting and maintaining home inotropic infusion while monitoring a challenging group of patients.

Immune checkpoint inhibitor-associated myocarditis: from pathophysiology to rechallenge of therapy - a narrative review.

Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.

Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

Haemodynamic effects of sacubitril/valsartan in advanced heart failure.

AIMS: The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, has been shown to be effective in treatment of patients with heart failure (HF), but limited data are available in patients with advanced disease. This retrospective observational study assessed the effects of ARNI treatment in patients with advanced HF. METHODS AND RESULTS: We reviewed medical records of all advanced HF patients evaluated at our centre for unconventional therapies from September 2016 to January 2019. We studied 44 patients who started ARNI therapy and who had a haemodynamic assessment before beginning ARNI and after 6 ± 2 months. The primary endpoint was variation in pulmonary pressures and filling pressures at 6 months after starting ARNI therapy. Mean patient age was 51.6 ± 7.4 years; 84% were male. At 6 ± 2 months after starting ARNI, there was significant reduction of systolic pulmonary artery pressure [32 mmHg, interquartile range (IQR) 27-45 vs. 25 mmHg, IQR 22.3-36.5; P < 0.0001] and mean pulmonary artery pressure (20 mmHg, IQR 15.3-29.8 vs. 17 mmHg, IQR 13-24.8; P = 0.046). Five of 22 patients (23%) were deferred from the heart transplant list because of improvement, whereas four were listed de novo. After 23 ± 9 months, three patients were treated with a left ventricular assist device implantation, whereas six patients underwent heart transplantation (one in emergency conditions for refractory ventricular tachycardia). CONCLUSIONS: Sacubitril/valsartan is effective in reducing filling pressures and pulmonary pressures in patients with advanced HF. The absence of adverse events during follow-up suggests that sacubitril/valsartan is safe and well-tolerated in this cohort of patients.

Heart Rate in Patients with SARS-CoV-2 Infection: Prevalence of High Values at Discharge and Relationship with Disease Severity.

The most common arrhythmia associated with COronaVIrus-related Disease (COVID) infection is sinus tachycardia. It is not known if high Heart Rate (HR) in COVID is simply a marker of higher systemic response to sepsis or if its persistence could be related to a long-term autonomic dysfunction. The aim of our work is to assess the prevalence of elevated HR at discharge in patients hospitalized for COVID-19 and to evaluate the variables associated with it. We enrolled 697 cases of SARS-CoV2 infection admitted in our hospital after February 21 and discharged within 23 July 2020. We collected data on clinical history, vital signs, laboratory tests and pharmacological treatment. Severe disease was defined as the need for Intensive Care Unit (ICU) admission and/or mechanical ventilation. Median age was 59 years (first-third quartile 49, 74), and male was the prevalent gender (60.1%). 84.6% of the subjects showed a SARS-CoV-2 related pneumonia, and 13.2% resulted in a severe disease. Mean HR at admission was 90 ± 18 bpm with a mean decrease of 10 bpm to discharge. Only 5.5% of subjects presented HR > 100 bpm at discharge. Significant predictors of discharge HR at multiple linear model were admission HR (mean increase = ß = 0.17 per bpm, 95% CI 0.11; 0.22, p < 0.001), haemoglobin (ß = -0.64 per g/dL, 95% CI -1.19; -0.09, p = 0.023) and severe disease (ß = 8.42, 95% CI 5.39; 11.45, p < 0.001). High HR at discharge in COVID-19 patients is not such a frequent consequence, but when it occurs it seems strongly related to a severe course of the disease.

Short- and long-term effects of a cardiac rehabilitation program in patients implanted with a left ventricular assist device.

The efficacy of cardiac rehabilitation in heart-failure patients who received a left-ventricular assist device (LVAD) instead of heart transplantation (HTx) is still unclear. This study aims to evaluate whether cardiac rehabilitation is beneficial in LVAD as HTx patients in the short term and whether its effects in LVAD patients persist over time. Twenty-five LVAD patients were evaluated by functional and psychological tests at admission (T0) and discharge (T1) of a 4-week inpatient structured rehabilitation program, and follow-ups 3 (T2), 6 (T3), and 12 months (T4) after discharge. Twenty-five matched HTx patients were also studied from T0 to T1 to compare the improvements in the six-minute walk test (6MWT). The quality-of-life scores substantially improved in LVAD patients and the 6MWT showed the same functional recovery as in HTx patients from T0 to T1. After T1, numerous LVAD patients withdrew from the study. However, the 6MWT outcome increased further from T1 to T3, with a positive trend during the follow-ups. Hemoglobin and the ventilatory performance increased, and the psychological perception of heart-failure symptoms and pain further improved at T2. In conclusion, exercise-based rehabilitation programs provide similar beneficial effects in LVAD and HTx patients, without deterioration in LVAD patients up to 12 months after discharge.

Innate Memory Reprogramming by Gold Nanoparticles Depends on the Microbial Agents That Induce Memory.

Innate immune memory, the ability of innate cells to react in a more protective way to secondary challenges, is induced by exposure to infectious and other exogeous and endogenous agents. Engineered nanoparticles are particulate exogenous agents that, as such, could trigger an inflammatory reaction in monocytes and macrophages and could therefore be also able to induce innate memory. Here, we have evaluated the capacity of engineered gold nanoparticles (AuNPs) to induce a memory response or to modulate the memory responses induced by microbial agents. Microbial agents used were in soluble vs. particulate form (MDP and the gram-positive bacteria Staphylococcus aureus; ß-glucan and the ß-glucan-producing fungi C. albicans), and as whole microrganisms that were either killed (S. aureus, C. albicans) or viable (the gram-negative bacteria Helicobacter pylori). The memory response was assessed in vitro, by exposing human primary monocytes from 2-7 individual donors to microbial agents with or without AuNPs (primary response), then resting them for 6 days to allow return to baseline, and eventually challenging them with LPS (secondary memory response). Primary and memory responses were tested as production of the innate/inflammatory cytokine TNFα and other inflammatory and anti-inflammatory factors. While inactive on the response induced by soluble microbial stimuli (muramyl dipeptide -MDP-, ß-glucan), AuNPs partially reduced the primary response induced by whole microorganisms. AuNPs were also unable to directly induce a memory response but could modulate stimulus-induced memory in a circumscribed fashion, limited to some agents and some cytokines. Thus, the MDP-induced tolerance in terms of TNFα production was further exacerbated by co-priming with AuNPs, resulting in a less inflammatory memory response. Conversely, the H. pylori-induced tolerance was downregulated by AuNPs only relative to the anti-inflammatory cytokine IL-10, which would lead to an overall more inflammatory memory response. These effects of AuNPs may depend on a differential interaction/association between the reactive particle surfaces and the microbial components and agents, which may lead to a change in the exposure profiles. As a general observation, however, the donor-to-donor variability in memory response profiles and reactivity to AuNPs was substantial, suggesting that innate memory depends on the individual history of exposures.

SERS Sensing of Bacterial Endotoxin on Gold Nanoparticles.

Engineered gold nanoparticles (AuNPs) find application in several fields related to human activities (i.e., food and cosmetic industry or water purification) including medicine, where they are employed for diagnosis, drug delivery and cancer therapy. As for any material/reagent for human use, the safety of AuNPs needs accurate evaluation. AuNPs are prone to contamination by bacterial endotoxin (lipopolysaccharide, LPS), a potent elicitor of inflammatory responses in mammals. It is therefore important, when assessing AuNP immunosafety and immune-related effects, to discriminate between inflammatory effects intrinsic to the NPs from those caused by an undeliberate and undetected LPS contamination. Detection of LPS contamination in AuNP preparations poses different problems when using the current LPS detection assays, given the general interference of NPs, similar to other particulate agents, with the assay reagents and endpoints. This leads to time-consuming search for optimal assay conditions for every NP batch, with unpredictable results, and to the use in parallel of different assays, each with its weaknesses and unpredictability. Thus, the development of highly sensitive, quantitative and accurate assays able to detect of LPS on AuNPs is very important, in view of their medical applications. Surface-enhanced Raman spectroscopy (SERS) is a label-free, sensitive, chemical-specific, nondestructive and fast technique that can be used to directly obtain molecular fingerprint information and a quantitative analysis of LPS adsorbed on AuNPs. Within this study, we describe the use of SERS for the label-free identification and quantitative evaluation - down to few attograms - of the LPS adsorbed on the surface of 50 nm AuNPs. We thus propose SERS as an efficient tool to detect LPS on the AuNP surface, and as the basis for the development of a new sensitive and specific LPS-detection sensor based on the use of AuNPs and SERS.

Long-term administration of intravenous inotropes in advanced heart failure.

BACKGROUND: Patients in heart transplantation (HTx) waiting list for advanced heart failure (HF) are susceptible to acute deterioration refractory to standard HF medical therapies. Limited data are available on long-term in-hospital continuous intravenous (IV) inotropic therapy as bridge to definite therapies. METHODS AND RESULTS: We reviewed medical records of all heart transplant recipients treated in the pre-HTx phase with in-hospital continuous IV inotropes at our institution between 2012 and 2018. We analysed data before the beginning of continuous IV therapy and at the moment of HTx. We report data of 24 patients (mean age of 43.5 ± 15.7 years) treated with IV inotropes as bridge to HTx (median follow-up of 28 months after HTx). The main length of IV inotropic therapy was 84 ± 66 days (min 22; max 264 days). At the beginning, the most frequently used inotrope was dopamine (median dosage of 3 mcg/kg/min, interquartile range 2.5-3.75), alone (n = 11, 46%) or in combination with other inotropes (n = 13, 54%). In 18 patients, the class of inotropes was changed during the hospitalization. We registered a progressive improvement of perfusion markers and neuro-hormonal activation. CONCLUSION: In-hospital continuous parenteral inotropic therapy may serve as a temporary pharmacological bridge to HTx in patients with advanced HF that are actively listed to HTx with good reply in terms of prognosis and perfusion markers.

Interaction of nanoparticles with endotoxin Importance in nanosafety testing and exploitation for endotoxin binding.

The interaction between engineered nanoparticles and the bacterial lipopolysaccharide, or endotoxin, is an event that warrants attention. Endotoxin is one of the most potent stimulators of inflammation and immune reactions in human beings, and is a very common contaminant in research labs. In nanotoxicology and nanomedicine, the presence of endotoxin on the nanoparticle surface affects their biological properties leading to misinterpretation of results. This review discusses the importance of detecting the endotoxin contamination on nanoparticles, focusing on the current method of endotoxin detection and their suitability for nanoparticulate materials. Conversely, the capacity of nanoparticles to bind endotoxin can be enhanced by functionalization with endotoxin-capturing molecules, opening the way to the development of novel endotoxin detection assays.

Interaction between Macrophages and Nanoparticles: In Vitro 3D Cultures for the Realistic Assessment of Inflammatory Activation and Modulation of Innate Memory.

Understanding the modes of interaction between human monocytes/macrophages and engineered nanoparticles is the basis for assessing particle safety, in terms of activation of innate/inflammatory reactions, and their possible exploitation for medical applications. In vitro assessment of nanoparticle-macrophage interaction allows for examining the response of primary human cells, but the conventional 2D cultures do not reproduce the three-dimensional spacing of a tissue and the interaction of macrophages with the extracellular tissue matrix, conditions that shape macrophage recognition capacity and reactivity. Here, we have compared traditional 2D cultures with cultures on a 3D collagen matrix for evaluating the capacity gold nanoparticles to induce monocyte activation and subsequent innate memory in human blood monocytes in comparison to bacterial LPS. Results show that monocytes react to stimuli almost in the same way in 2D and 3D cultures in terms of production of TNFα and IL-6, but that notable differences are found when IL-8 and IL-1Ra are examined, in particular in the recall/memory response of primed cells to a second stimulation, with the 3D cultures showing cell activation and memory effects of nanoparticles better. In addition, the response variations in monocytes/macrophages from different donors point towards a personalized assessment of the nanoparticle effects on macrophage activation.

Clarification of Misleading Perceptions of COVID-19 Fatality and Testing Rates in Italy: Data Analysis.

BACKGROUND: The fatality rate of coronavirus disease (COVID-19) in Italy is controversial and is greatly affecting discussion on the impact of containment measures that are straining the world's social and economic fabric, such as instigating large-scale isolation and quarantine, closing borders, imposing limits on public gatherings, and implementing nationwide lockdowns. OBJECTIVE: The scientific community, citizens, politicians, and mass media are expressing concerns regarding data suggesting that the number of COVID-19-related deaths in Italy is significantly higher than in the rest of the world. Moreover, Italian citizens have misleading perceptions related to the number of swab tests that have actually been performed. Citizens and mass media are denouncing the coverage of COVID-19 swab testing in Italy, claiming that it is not in line with that in other countries worldwide. METHODS: In this paper, we attempt to clarify the aspects of COVID-19 fatalities and testing in Italy by performing a set of statistical analyses that highlight the actual numbers in Italy and compare them with official worldwide data. RESULTS: The analysis clearly shows that the Italian COVID-19 fatality and mortality rates are in line with the official world scenario, as are the numbers of COVID-19 tests performed in Italy and in the Lombardy region. CONCLUSIONS: This up-to-date analysis may elucidate the evolution of the COVID-19 pandemic in Italy.

Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance.

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.

Gold nanoparticles modulate BCG-induced innate immune memory in human monocytes by shifting the memory response towards tolerance

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFa, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.

Gold nanoparticles modulate BCG-induced innate immune memory in human monocytes by shifting the memory response towards tolerance

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFa, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.

Scheduled intermittent inotropes for Ambulatory Advanced Heart Failure. The RELEVANT-HF multicentre collaboration.

BACKGROUND: Ambulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients. METHODS: 185 AAHF NYHA class III-IV patients, with ≥2 HF hospitalizations/emergency visits in the previous 6 months and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2 µg/kg/min) without prior bolus every 3-4 weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6 months before and after treatment start. RESULTS: Infusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6 months before to the 6 months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p < 0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), p = 0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, p = 0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant. CONCLUSIONS: In AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.

Graphene-Based Raman Spectroscopy for pH Sensing of X-rays Exposed and Unexposed Culture Media and Cells.

Graphene provides a unique way of sensing the local pH level of substances on the micrometric scale, with important implications for the monitoring of cellular metabolic activities where proton excretion could occur. Accordingly, an innovative biosensing approach for the quantification of the pH value of biological fluids, to be used also with small amounts of fluids, was realized and tested. It is based on the use of micro-Raman spectroscopy to detect the modifications of the graphene doping level induced by the contact of the graphene with the selected fluids. The approach was preliminarily tested on aqueous solutions of known pH values. It was then used to quantify the pH values of cell culture media directly exposed to different doses of X-ray radiation and to media exposed to X-ray-irradiated cells. The Raman response of cells placed on graphene layers was also examined.