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Human cytomegalovirus (HCMV) causes congenital neurological lifelong disabilities. To date, the neuropathogenesis of brain injury related to congenital HCMV (cCMV) infection is poorly understood. This study evaluates the characteristics and pathogenetic mechanisms of encephalic damage in cCMV infection. Ten HCMV-infected human fetuses at 21 weeks of gestation were examined. Specifically, tissues from different brain areas were analyzed by: (i) immunohistochemistry (IHC) to detect HCMV-infected cell distribution, (ii) hematoxylin–eosin staining to evaluate histological damage and (iii) real-time PCR to quantify tissue viral load (HCMV-DNA). The differentiation stage of HCMV-infected neural/neuronal cells was assessed by double IHC to detect simultaneously HCMV-antigens and neural/neuronal markers: nestin (a marker of neural stem/progenitor cells), doublecortin (DCX, marker of cells committed to the neuronal lineage) and neuronal nuclei (NeuN, identifying mature neurons). HCMV-positive cells and viral DNA were found in the brain of 8/10 (80%) fetuses. For these cases, brain damage was classified as mild (n = 4, 50%), moderate (n = 3, 37.5%) and severe (n = 1, 12.5%) based on presence and frequency of pathological findings (necrosis, microglial nodules, microglial activation, astrocytosis, and vascular changes). The highest median HCMV-DNA level was found in the hippocampus (212 copies/5 ng of human DNA [hDNA], range: 10–7,505) as well as the highest mean HCMV-infected cell value (2.9 cells, range: 0–23), followed by that detected in subventricular zone (1.7 cells, range: 0–19). These findings suggested a preferential viral tropism for both neural stem/progenitor cells and neuronal committed cells, residing in these regions, confirmed by the expression of DCX and nestin in 94% and 63.3% of HCMV-positive cells, respectively. NeuN was not found among HCMV-positive cells and was nearly absent in the brain with severe damage, suggesting HCMV does not infect mature neurons and immature neural/neuronal cells do not differentiate into neurons. This could lead to known structural and functional brain defects from cCMV infection. Graphical Abstract

Despite recent advances in chronic heart failure (HF) therapy, the prognosis of HF patients remains poor, with high rates of HF rehospitalizations and death in the early months after discharge. This emphasizes the need for incorporating novel HF drugs, beyond the current approach (that of modulating the neurohumoral response). Recently, new antidiabetic oral medications (sodium-glucose cotransporter 2 inhibitors (SGLT2i)) have been shown to improve prognosis in diabetic patients with previous cardiovascular (CV) events or high CV risk profile. Data from DAPA-HF study showed that dapaglifozin is associated with a significant reduction in mortality and HF hospitalization as compared with placebo regardless of diabetes status. Recently, results from EMPEROR-Reduced HF trial were consistent with DAPA-HF trial findings, showing significant beneficial effect associated with empagliflozin use in a high-risk HF population with markedly reduced ejection fraction. Results from the HF with preserved ejection fraction trials using these same agents are eagerly awaited. This review summarizes the evidence for the use of gliflozins in HF treatment.

Assessing the safety of SARS-CoV-2 mRNA vaccines and the effect of immunotherapies on the seroconversion rate in patients with autoimmune neurological conditions (ANC) is relevant to clinical practice. Our aim was to assess the antibody response to and safety of SARS-CoV-2 mRNA vaccines in ANC.This longitudinal study included ANC patients vaccinated with two doses of BNT162b2 or mRNA-1273 between March and August 2021. Side effects were assessed 2-10 days after each dose. Neurological status and anti-spike receptor binding domain antibody levels were evaluated before vaccination and 4 weeks after the second dose. Healthcare-workers served as controls for antibody levels.We included 300 ANC patients (median age 52, IQR 40-65), and 347 healthcare-workers (median age 45, IQR 34-54). mRNA-1273 vaccine was associated with an increased risk of both local (OR 2.52 95% CI 1.45-4.39, p = 0.001) and systemic reactions (OR 2.51% CI 1.49-4.23, p = 0.001). The incidence of relapse was not different before and after vaccine (Incidence rate ratio 0.72, 95% CI 0.29-1.83). Anti-SARS-CoV-2 IgG were detected in 268 (89.9%) patients and in all controls (p 0.0001). BNT162b2 vaccine (OR 8.84 95% CI 2.32-33.65, p = 0.001), anti-CD20 mAb (OR 0.004 95% CI 0.0007-0.026, p 0.0001) and fingolimod (OR 0.036 95% CI 0.002-0.628, p = 0·023) were associated with an increased risk of not developing anti-SARS-CoV-2 IgG.SARS-CoV-2 mRNA vaccines were safe in a large group of ANC patients. Anti-CD20 and fingolimod treatment, as well as vaccination with the BNT162b2 vaccine, led to a reduced humoral response. These findings could inform vaccine policies in ANC patients undergoing immunotherapy.

Aims Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of hypoglycemic agents for type 2 diabetes mellitus (T2DM), which act independently of insulin to selectively inhibit renal glucose reabsorption, thereby increasing urinary excretion of glucose. Several studies have demonstrated the cardioprotective effects of SGLT2-i in patients with heart failure (HF), with and without diabetes mellitus. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of left or right ventricular function in patients affected by HF with T2DM. Evaluate the effect of SGLT2 inhibitors on left and right ventricular function by conventional and advanced echocardiographic parameters, focusing on speckle tracking echocardiography, in patients with HF and T2DM. Methods and results BEGIN-HF is an international multi-centre registry enrolling outpatients affected by HF and T2DM. Inclusion criteria are HbA1c> 6.5%, eGFR [MDRD] > 45 ml/min/1.73 m2, age > 18 years, FE Conclusions This is the first international multicentre registry evaluating biventricular function by conventional and advanced echocardiography in patients with HF and T2DM starting and no-starting SGLT2i therapy.

Background/Aim: The renal arterial resistance index (RRI) is a Doppler measure, which reflects abnormalities in the renal blood flow. The aim of this study was to verify the value of RRI as a predictor of worsening renal function (WRF) in a group of chronic heart failure (CHF) outpatients. Methods: We enrolled 266 patients in stable clinical conditions and on conventional therapy. Peak systolic velocity and end diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow, and RRI was calculated. Creatinine serum levels were evaluated at baseline and at 1 year, and the changes were used to assess WRF occurrence. Results: During follow-up, 34 (13%) patients showed WRF. RRI was associated with WRF at univariate (OR: 1.13; 95% CI: 1.07-1.20) as well as at a forward stepwise multivariate logistic regression analysis (OR: 1.09; 95% CI: 1.03-1.16; p = 0.005) including the other univariate predictors. Conclusions: Quantification of arterial renal perfusion provides a new parameter that independently predicts the WRF in CHF outpatients. Its possible role in current clinical practice to better define the risk of cardiorenal syndrome progression is strengthened.

Aim of the study: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. Methods: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. Results: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04, 95% CI: 2.14&ndash, 7.65, p &lt, 0.001), pattern D (HR 7.16, 95% CI: 3.69&ndash, 13.9, 0.001) and pattern E (HR 8.94, 95% CI: 4.65&ndash, 17.2, 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79, 95% CI: 1.09&ndash, 2.97, p: 0) and of pattern D or E (HR: 1.90, 95% CI: 1.16&ndash, 3.12, p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46, 95% CI 0.24&ndash, 0.68, 0.001). Conclusions: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome.

Despite recent advances in chronic heart failure treatment, prognosis of acute heart failure patients remains poor with a heart failure rehospitalization rate or death reaching approximately 25% during the first 6 months after discharge. In addition, about half of these patients have preserved ejection fraction for which there are no evidence-based therapies. Disappointing results from heart failure clinical trials over the past 20 years emphasize the need for developing novel approaches and pathways for testing new heart failure drugs and devices. Indeed, many trials are being conducted without matching the mechanism and action of the drug with the clinical event. The implementation of these novel approaches should be coupled with the training of a new generation of heart failure physicians and scientists in the art and science of clinical trials. Currently, drug development is led by opinion leaders and experts who, despite their huge personal experience, were never trained systematically on drug development. The aim of this article is to propose a training program of 'drug development in Heart Failure'. A physician attending this course would have to be trained with a major emphasis on heart failure pathophysiology to better match mechanisms of death and rehospitalization with mechanism of action of the drug. Applicants will have to prove their qualifications and special interest in heart failure drug development before enrollment. This article should serve as a roadmap on how to apply emerging general principles in an innovative drug-development-in-heart-failure-process as well as the introduction of a new educational and mentorship program focusing on younger generations of researchers.

The assessment of right ventricular (RV) function still remains a challenge. Two-dimensional (2D) speckle tracking has recently been proposed to evaluate right ventricular function by analyzing myocardial deformation. The aim of this study was to evaluate the role of 2D systolic strain measures of RV in predicting mortality in patients with chronic heart failure (HF). We enrolled 332 outpatients in a stable clinical condition and in conventional therapy. A right ventricular-focused four-chamber view was analyzed by 2D speckle tracking to evaluate the global longitudinal strain of RV (RV-GLS) and the strain of RV free wall (RV-fwLS). During a mean follow-up of 36 ± 26 months, 64 patients died. Both RV-GLS and RV-fwLS were associated with all-cause mortality in univariate (HR: 1.16; 95% CI: 1.10-1.23; P < 0.001; C-index: 0.72; and HR: 1.10; 95% CI: 1.06-1.15; P < 0.001; C-index: 0.68, respectively) as well as multivariate analysis (HR: 1.13; 95% CI: 1.05-1.21; P:0.001; C-index: 0.85; and HR: 1.07; 95% CI: 1.02-1.12; P:0.004; C-index: 0.84, respectively). In conclusion, our findings demonstrate the role of RV 2D strain measures to independently predict mortality. These data highlight the clinical usefulness of this echocardiographic approach in the daily management of HF outpatients.

A política de alimentação escolar, implementada por meio do Programa Nacional de Alimentação Escolar PNAE é um dos programas sociais mais antigos do país e de grande relevância para o atendimento ao educando da rede pública de ensino, vis-à-vis as enormes desigualdades sociais e regionais peculiares ao federalismo brasileiro. A implementação local desta política assume formatos diversos sob as modalidades de descentralização da gestão adotadas pelos próprios governos locais. Desta forma, a presente dissertação teve como objetivo principal analisar qualitativamente a implementação do PNAE, produzidos por diferentes modalidades de descentralização, a partir da classificação de parâmetros representados em termos de capacidades técnicas mobilizadas, de eficiência financeira e de accountability social, com a finalidade de averiguar semelhanças e diferenças nestes modelos e suas implicações na qualidade da política. Para isso, admite-se como pressuposto que distintas combinações da descentralização tendem a produzir diferentes resultados para a vida política local, bem como distintos resultados em políticas específicas. A proposta metodológica consiste em uma análise qualitativa da gestão do PNAE, nos anos 2013 a 2015, em termos dos resultados de sua operacionalização no sistema público de ensino das capitais brasileiras, comparando-as ao tomar, como variável independente, as distintas modalidades de gestão adotadas em cada esfera municipal: escolarização, municipalização ou mista, as quais podem ser mescladas com a possibilidade de terceirização ou não. A variável dependente teve como marcadores os mecanismos de accountability, as capacidades técnicas mobilizadas e a eficiência financeira do Programa, mensurados por parâmetros e indicadores. A fonte dos dados dos indicadores selecionados foi disponibilizada pelo Sistema de Gestão de Prestação de Contas (SigPC) do Fundo Nacional de Desenvolvimento da Educação, de acesso público, por meio do questionário respondido pelo Conselho de Alimentação Escolar (CAE) e pela Entidade Executora (EEx), bem como por outros dispositivos de informação deste sistema. A análise da pesquisa proposta nos permitiu concluir que as modalidades de gestão desta política nas capitais, em virtude do pequeno escopo de análise, em pouco traduzem a complexidade das relações federativas no Brasil, mas nos possibilita perceber que, em termos de sua implementação, ainda há nós que precisam ser desatados para o seu efetivo atendimento. The school feeding policy, which is implemented by the National School Feeding Programme (PNAE) - is one of the oldest social programmes in the country and it is fully important for the care of students in the public-school system, considering such enormous social and regional inequalities peculiar to Brazilian federalism. The implementation of this policy takes different forms in models on decentralization of management adopted by local governments who assume the implementation of the program. Thus, the present research aimed to analyze the effects on the implementation of the PNAE, produced by different modalities of decentralization, based on the classification of parameters represented in terms of mobilized technical capacities, financial efficiency and social accountability, for the purpose to identify similarities and differences in these models and their implications for the quality of politics. For this, we assume that different combinations of decentralization tend to produce different results for local political life, as well as different results in specific policies. The methodological proposal consists of a qualitative analysis on the management of the PNAE, from 2013 to 2015, in terms of the results of its operational framework in the public-school system in Brazilian capitals, comparing them and taking, as independent variable, the different management models chosen in each municipal sphere: centralized model, decentralized model, mixed models, which can be insourced or outsourced ones. The dependent variable had as markers the mechanisms of accountability, the mobilized technical capacities and the financial efficiency of the Program, measured by parameters and indicators. The data source of the selected indicators were available by the Public Account Management System (SiGPC) of the National Fund for Development of Education, by a questionnaire answered by the School Feeding Council (CAE) and by the Executing Agency (Municipal Secretariat of Education), as well as other information devices of this system. As result, the proposed research has allowed us to conclude that the management models of this policy in capitals, due to the small scope of analysis, do not translate the complexity of federative relations in Brazil, but it allows us to realize that, in terms of its implementation, there are still obstacles that need to be solved for their effective service.

Background: In chronic heart failure (CHF) patients there is a wide variability in the minimal effective diuretic dose. The aim of this study is to evaluate whether renal resistance index (RRI) is associated to baseline diuretic dose and the changes at one year. Methods and results: 250 outpatients in a stable condition and in conventional therapy were enrolled. Baseline RRI was calculated by renal arterial Doppler. The total daily dose of loop diuretics was assessed at baseline and after one year. High diuretic dose (HDD) was defined as a daily furosemide equivalent dose >100 mg. RRI was independently associated with baseline HDD at univariate (OR 1.39; 95% CI: 1.233–1.58; p

To evaluate whether right ventriculo-arterial coupling obtained by the estimation of the two-dimensional right ventricular (RV) longitudinal strain and of the pulmonary arterial systolic pressure (PASP) could improve prognostic stratification of chronic heart failure (CHF) outpatients.CHF outpatients in a stable clinical condition and in conventional therapy were enrolled. The global RV longitudinal strain (RV-GLS) and the strain of the RV free wall (RV-fwLS) were evaluated. PASP was estimated on the basis of tricuspid regurgitation velocity and the estimated central venous pressure. Both RV-GLS and RV-fwLS were then indexed for PASP.Of the 315 patients evaluated, 69 died during follow-up. Both RV-GLS/PASP and RV-fwLS/PASP were significantly associated with an increased risk of death at univariate (HR: 0.43; 95%CI: 0.34-0.56; p0.001 and HR: 0.44; 95% CI: 0.34-0.57; p0.001, respectively) and multivariate analysis (HR: 0.66; 95% CI: 0.49-0.89; p: 0.008 and HR: 0.65; 95% CI: 0.49-0.85; p: 0.002, respectively) after correction for age, NYHA class, mean arterial pressure, left ventricular ejection fraction, natremia, glomerular filtration rate and NT-proBNP.Indexing RV function, assessed by speckle-tracking analysis, with an estimation of pulmonary systolic arterial pressure provides a parameter of ventricular arterial coupling that is independently associated with an increased risk of mortality.

Over the last years a number of new biomarkers reflecting different aspects of heart failure (HF) pathophysiology have been evaluated in order to improve diagnosis and to better define prognosis of patients. Among these, Galectin 3 (Gal-3) seems particularly promising. It is a soluble beta galactoside-binding lectin produced by activated macrophages which binds and activates the fibroblasts thus leading to the deposition of collagen into the extracellular matrix and to a progressive cardiac fibrosis. Gal-3 plays also an important regulatory role in inflammatory status. Experimental studies have demonstrated that it is involved in cardiac remodeling and that it is one of the main determinants of development and progression of HF. In humans, Gal-3 plasma levels are associated with the onset of HF in apparently healthy patients and have been found being predictors of a worse prognosis in acute (AHF) as well as in chronic heart failure (CHF). Furthermore, Gal-3 serum levels are strongly correlated with renal dysfunction thus suggesting a possible role in better characterizing cardiorenal syndrome. The aim of this review was to revise the available experimental and clinical data concerning the role of Gal-3 as prognostic marker in HF.

Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave (QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice.

Chronic kidney disease and its worsening are recurring conditions in chronic heart failure (CHF) which are independently associated with poor patient outcome. The heart and kidney share many pathophysiological mechanisms which can determine dysfunction in each organ. Cardiorenal syndrome is the condition in which these two organs negatively affect each other, therefore an accurate evaluation of renal function in the clinical setting of CHF is essential. This review aims to revise the parameters currently used to evaluate renal dysfunction in CHF with particular reference to the usefulness and the limitations of biomarkers in evaluating glomerular dysfunction and tubular damage. Moreover, it is reported the possible utility of renal arterial resistance index (a parameter associated with abnormalities in renal vascular bed) for a better assesment of kidney disfunction.