Do you agree with the doctor’s decision to continue treatment? A scenario-based study of hospital nurses in Italy

Introduction. A lack of social consensus on the duty to comply with a patient’s request to forgo treatment was reported in Italy, but little is known about the nurses’ attitudes regarding this issue. Materials and methods. Questionnaire including two clinical scenarios regarding doctor’s decision to not comply with a competent patient’s request to forgo treatment was administered to all nurses (n=487) of an Italian medium-sized hospital. Results. Eighty-five percent of nurses completed the study. Although 83% of participants supported a general right to self-determination, around 40% of them agreed with the doctor’s decision in both scenarios. The multivariate analyses adjusted for gender, age, length of professional experience, and care setting showed that the agreement with the doctor’s decision was significantly associated with nurses’ personal background beliefs about self-determination and quality of life. Discussion and Conclusions. Many nurses have difficulty in accepting a patient’s request to forgo treatment. Increasing ethical reflection and discussion at both educational and professional level, and introducing ethical consultation services would be essential to develop a consistent approach to end-of-life decisions in Italian hospitals.

A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy

T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II–mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast to IFN-γ−/− mice that are protected from CAV, T-bet−/− recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17–producing CD4 T cells. Concurrently, T-bet−/− mice exhibit a T helper type 1 (Th1)–deficient environment characterized by profound IFN-γ deficiency, a Th2 switch characterized by increased production of interleukin (IL) 4, IL-5, IL-10, and IL-13 cytokines, as well as increased production of the proinflammatory cytokines IL-6, IL-12p40, and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection and vasculopathy in T-bet−/− mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet−/− mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first study establishing that in the absence of Th1-mediated alloimmune responses, CD4 Th17 cells mediate an aggressive proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for the development of novel therapies to target this intractable problem in clinical solid organ transplantation

A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice

OBJECTIVE - To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent alloand autoimmune activation using a stringent model of islet transplantation and diabetes reversal. RESEARCH DESIGN AND METHODS - Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. RESULTS - BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice). CONCLUSIONS - The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes

Predictors of Response to Hydroxyurea and Switch to Ruxolitinib in HU-Resistant Polycythaemia VERA Patients: A Real-World PV-NET Study

In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p &lt; 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised

ATG based combination therapy - a novel clinically relevant approach to promote regulation and induce long-term allograft survival

Regulatory T cells (Treg) actively regulate alloimmune responses and promote transplantation tolerance. Polyclonal anti-thymocyte globulin (ATG), a widely used induction therapy in clinical organ transplantation, depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T cell depleting strategies and is attributed to alterations in the balance of naïve, memory and regulatory T cells. Here we report a novel reagent, murine ATG (mATG), depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T cell repertoire toward T-effector-memory (Tem) phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and Sirolimus synergize to prolong graft survival by tipping the Treg/Tem balance further in favor of Tregs by preserving Tregs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation. These results provide the rationale for translating such novel combination therapies to promote tolerance in primate and human organ transplantation

Eficacia de la política monetaria: un análisis conceptual y matemático basado en el modelo IS-LM

CD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8(+) cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4(+) or CD8(+) T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8(+) T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4(-/-), CD28(-/-) knockout and CTLA4Ig treated WT recipients, but not in WT or CD8(-/-) knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8(+) T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection

A machine learning approach to characterize patients with asthma exacerbation attending an acute care setting

One of the main problems in poorly controlled asthma is the access to the Emergency Department (ED). Using a machine learning (ML) approach, the aim of our study was to identify the main predictors of severe asthma exacerbations requiring hospital admission

Metabolic-associated fatty liver disease from childhood to adulthood: State of art and future directions

In 2020, an international group of experts proposed to replace the term of nonalcoholic fatty liver disease with metabolic-associated fatty liver disease (MAFLD). This recent proposal reflects the close association of fatty liver with metabolic derangements, as demonstrated by previous robust data. Several factors [including genetics, inflammation, metabolic abnormalities, insulin resistance (IR), obesity, prenatal determinants, and gut-liver axis] have been found to be involved in MAFLD pathophysiology, but this tangled puzzle remains to be clearly understood. In particular, IR has been recognized as a key player in metabolic impairments development in children with fatty liver. On this ground, MAFLD definition focuses on the pathophysiological basis of the disease, by emphasizing the crucial role of metabolic impairments in this condition. Although primarily developed for adults, MAFLD diagnostic criteria have been recently updated with an age-appropriate definition for sex and age percentiles, because of the increasing attention to cardiometabolic risk in childhood. To date, accumulating evidence is available on the feasibility of MAFLD definition in clinical practice, but some data are still conflicting in highly selected populations. Considering the growing prevalence worldwide of fatty liver and its close relationship with metabolic dysfunction both in children and adults with subsequent increased cardiovascular risk, early strategies for MAFLD identification, treatment and prevention are needed. Novel therapeutic insights for MAFLD based on promising innovative biological techniques are also emerging. We aimed to summarize the most recent evidence in this intriguing research area both in children and adults

An in vivo autotransplant model of renal preservation: cold storage versus machine perfusion in the prevention of ischemia/reperfusion injury

There is increasing proof that organ preservation by machine perfusion is able to limit ischemia/reperfusion injury in kidney transplantation. This study was designed to compare the efficiency in hypothermic organ preservation by machine perfusion or cold storage in an animal model of kidney autotransplantation. Twelve pigs underwent left nephrectomy after warm ischemic time; the organs were preserved in machine perfusion (n = 6) or cold storage (n = 6) and then autotransplanted with immediate contralateral nephrectomy. The following parameters were compared between the two groups of animals: hematological and urine indexes of renal function, blood/gas analysis values, histological features, tissue adenosine-5'-triphosphate (ATP) content, perforin gene expression in kidney biopsies, and organ weight changes were compared before and after preservation. The amount of cellular ATP was significantly higher in organs preserved by machine perfusion; moreover, the study of apoptosis induction revealed an enhanced perforin expression in the kidneys, which underwent simple hypothermic preservation compared to the machine-preserved ones. Organ weight was significantly decreased after cold storage, but it remained quite stable for machine-perfused kidneys. The present model seems to suggest that organ preservation by hypothermic machine perfusion is able to better control cellular impairment in comparison with cold storage