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N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC’s interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC’s in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300–345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.

Background The contagiousness of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is known to be linked to the emission of bioaerosols. Thus, aerosol-generating procedures (AGPs) could increase the risk of infection among healthcare workers (HCWs). Aim To investigate the impact of an aerosol protection box, the SplashGuard Caregiver (SGGC) with suction system, by direct analysis of the presence of viral particles after an AGP, and by using the computational fluid dynamics (CFD) simulation method. Methods This prospective observational study investigated HCWs caring for patients with SARS-CoV-2 admitted to an intensive care unit (ICU). Rooms were categorized as: SGCG present and SGCG absent. Virus detection was performed through direct analysis, and using a CFD model to simulate the movement dynamics of airborne particles produced by a patient's respiratory activities. Findings Of the 67 analyses performed, three samples tested positive on quantitative polymerase chain reaction: one of 33 analyses in the SCCG group (3%) and two of 34 analyses in the non-SGCG group (5.9%). CFD simulations showed that: (1) reduction of the gaps of an SGCG could decrease the number of emitted particles remaining airborne within the room by up to 70%; and (2) positioning HCWs facing the opposite direction to the main air flow would reduce their exposure. Conclusions This study documented the presence of SARS-CoV-2 among HCWs in a negative pressure ICU room of an infected patient with or without the use of an SGCG. The simulation will help to improve the design of the SGCG and the positioning of HCWs in the room.

Background and ObjectiveThis was a multicenter study aimed at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre-mild cognitive impairment [pre-MCI]).MethodsData were obtained from the Network-AD project (NET-2011-02346784). The included participants underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and amyloid PET. We used principal component analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism.ResultsA total of 105 participants (SCD = 49, pre-MCI = 56) were included. FDG-PET was normal in 45% of participants and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the participants who underwent amyloid PET (n = 60). PCA resulted in 3 neuropsychological factors: (1) executive/visuomotor, correlating with hypometabolism in frontal and occipital cortices and basal ganglia; (2) memory, correlating with hypometabolism in temporoparietal regions; and (3) visuospatial/constructional, correlating with hypometabolism in frontoparietal cortices. Two factors emerged from the neuropsychiatric PCA: (1) affective, correlating with hypometabolism in orbitofrontal and cingulate cortex and insula; (2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal, and parietal regions.DiscussionFDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre-MCI. These results indicate that SCD and pre-MCI represent heterogeneous populations. Different neuropsychological and neuropsychiatric profiles emerged, which correlated with neu

Deep learning (DL) strategies applied to magnetic resonance (MR) images in positron emission tomography (PET)/MR can provide synthetic attenuation correction (AC) maps, and consequently PET images, more accurate than segmentation or atlas-registration strategies. As first objective, we aim to investigate the best MR image to be used and the best point of the AC pipeline to insert the synthetic map in. Sixteen patients underwent a 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) and a PET/MR brain study in the same day. PET/CT images were reconstructed with attenuation maps obtained: (1) from CT (reference), (2) from MR with an atlas-based and a segmentation-based method and (3) with a 2D UNet trained on MR image/attenuation map pairs. As for MR, T1-weighted and Zero Time Echo (ZTE) images were considered; as for attenuation maps, CTs and 511 keV low-resolution attenuation maps were assessed. As second objective, we assessed the ability of DL strategies to provide proper AC maps in presence of cranial anatomy alterations due to surgery. Three 11C-methionine (METH) PET/MR studies were considered. PET images were reconstructed with attenuation maps obtained: (1) from diagnostic coregistered CT (reference), (2) from MR with an atlas-based and a segmentation-based method and (3) with 2D UNets trained on the sixteen FDG anatomically normal patients. Only UNets taking ZTE images in input were considered. FDG and METH PET images were quantitatively evaluated. As for anatomically normal FDG patients, UNet AC models generally provide an uptake estimate with lower bias than atlas-based or segmentation-based methods. The intersubject average bias on images corrected with UNet AC maps is always smaller than 1.5%, except for AC maps generated on too coarse grids. The intersubject bias variability is the lowest (always lower than 2%) for UNet AC maps coming from ZTE images, larger for other methods. UNet models working on MR ZTE images and generating synthetic CT or 511 k

The reference standard for spatial normalization of brain positron emission tomography (PET) images involves structural Magnetic Resonance Imaging (MRI) data. However, the lack of such structural information is fairly common in clinical settings. This might lead to lack of proper image quantification and to evaluation based only on visual ratings, which does not allow research studies or clinical trials based on quantification. PET/CT systems are widely available and CT normalization procedures need to be explored. Here we describe and validate a procedure for the spatial normalization of PET images based on the low-dose Computed Tomography (CT) images contextually acquired for attenuation correction in PET/CT systems. We included N = 34 subjects, spanning from cognitively normal to mild cognitive impairment and dementia, who underwent amyloid-PET/CT (18F-Florbetaben) and structural MRI scans. The proposed pipeline is based on the SPM12 unified segmentation algorithm applied to low-dose CT images. The validation of the normalization pipeline focused on 1) statistical comparisons between regional and global 18F-Florbetaben-PET/CT standardized uptake value ratios (SUVrs) estimated from both CT-based and MRI-based normalized PET images (SUVrCT SUVrMRI) and 2) estimation of the degrees of overlap between warped gray matter (GM) segmented maps derived from CT- and MRI-based spatial transformations. We found negligible deviations between regional and global SUVrs in the two CT and MRI-based methods. SUVrCT and SUVrMRI global uptake scores showed negligible differences (mean ± sd 0.01 ± 0.03). Notably, the CT- and MRI-based warped GM maps showed excellent overlap (90% within 1 mm). The proposed analysis pipeline, based on low-dose CT images, allows accurate spatial normalization and subsequent PET image quantification. A CT-based analytical pipeline could benefit both research and clinical practice, allowing the recruitment of larger samples and favoring clinical routine a

Pain activates a general hormonal and inflammatory reaction is a main determinant in postsurgical patient’s recovery that may negatively affect the CV system, especially in high-risk patients. Pain can also become chronic, increasing the risk for CV dysfunctions. Epidural analgesia has various beneficial effects on patient’s outcome, including the reduction of stress response and sympathetic activation after surgery. Some data suggest a protective role of EA on CV morbidity, especially on ischemia and dysrhythmias. However, serious CV complications may be expected with neuraxial anesthesia. Traditional CV drugs such as alpha-2 agonists and beta-blockers display important role in pain treatment. Clonidine may also protect from CV morbidity perioperatively, by improving hemodynamic and sympathetic stabilities and reducing stress response, while beta-blockers display beneficial effects in cardiac surgery but may be deleterious in noncardiac surgery. On the other hand, common drugs that are effective for analgesia may also improve the risk for CV morbidity. COX-2 inhibitors are contraindicated for chronic use in pain patients; however, they may not be unsafe in the perioperative setting. Available data are sparse to conclude that short-time administration of COX-2 inhibitors in the perioperative setting is associated to higher risk of CV morbidity, except for patients at higher risk for cardiac events. As well, new data suggest that acetaminophen, which is traditionally considered safe in terms of CV risk, may not be as safe as believed. Opioids are safe, but can harm CV homeostasis in specific cases or when associated with other drugs; neuraxial opioids may protect from hemodynamic impairment and positively affect analgesia. Protecting heart function during pain flares means acting on nociceptive stimulus and on the organic response to pain; the concept should be to stabilize and bring homeostasis to a pain patient’s CV system, always balancing beneficial and detriment

Transition from stage C to stage D of heart failure (HF) represents an irreversible process toward end-stage disease. Crucial interventions to be adopted in the attempt to interfere with this process are represented by the identification of patients at high risk to develop HF progression and by an effective and prompt management. Markers of worse prognosis and disease progression are well established and include recurrence of HF decompensation, intolerance to the neurohormonal standard pharmacological treatment, and resistance to loop diuretics. In addition, both NT-proBNP and sympathetic nervous system (SNS) overdrive are strong predictors of adverse clinical outcome and allow to identify high-risk HF patients even in the presence of mild symptoms. To counteract the deleterious effects of the SNS activation, new strategies such as a new drug combining angiotensin receptor and neprilysin inhibition and baroreceptor stimulation therapy (BAT) have been investigated. Inability to properly counteract the SNS overdrive leads to acute HF decompensation by different mechanisms. The leading ones are represented by the progressive sodium and water retention with fluid overload and by the blood volume redistribution between splanchnic and non-splanchnic regions. The correct understanding of these mechanisms, together with the availability of new therapeutic options such as peritoneal ultrafiltration, represent the rationale but not infrequently overlooked therapeutic options to improve congestion management in HF patients.

Aims The aim is to investigate autonomic nervous system imbalance in hypertrophic cardiomyopathy (HCM) by combining echocardiographic morphological and functional parameters with the analysis of the autonomic responses to orthostatic stress. Methods A 10-min tilting test and a transthoracic echocardiogram focused on ventricular septal systolic (S wave) and diastolic function (isovolumic relaxation time) were performed. Low frequency on high frequency ratio (LF/HF) and RR variation (variation of beat to beat intervals) in response to passive orthostatism were used as measures of sympathetic reflex activation [delta LF/HF (D-LF/HF) and delta RR (DRR), respectively]. Brain natriuretic peptide was measured. Results A total of 50 HCM patients were categorized in two groups: D-LF/HF more than 0 (group 1, sympathetic response) and D-LF/HF 0 or less (group 2, parasympathetic response). Patients in group 2 had higher New York Heart Association class, a more frequent history of atrial fibrillation (38 versus 9% P = 0.04) or syncope (46 versus 12% P = 0.01) and an increased septal isovolumic relaxation time (122 versus 82 ms P = 0.02). The same categorization was made according to lowest quartile DRR (DRR at least 23 ms, group 1: sympathetic response; DRR less than 23 ms, group 2: parasympathetic response). In group 2, patients were older, with advanced New York Heart Association class and higher history of atrial fibrillation. Conclusions Autonomic response to passive orthostatism in HCM appears correlated with specific functional features of the hypertrophic heart. Altered neural afferent traffic from the localized area of segmental hypertrophy resulted in autonomic changes with a blunted sympathetic response, and an inappropriate vagal activation, especially in patients with history of atrial fibrillation or syncope.

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

Cardiovascular disease (CVD) has been proven to be the largest contributor to morbidity and mortality in the developed world. By considering the psychosocial factors that have been linked to CVD, this chapter will focus on the role of psychological distress. Existing empirical evidence shows that stress can be considered as a risk factor starting from the early years, while in adulthood the risk associated with distress derives mainly from either social isolation or workplace-related chronic stressors. Both behavioral and neurobiological mechanisms have been proposed to underlie this association, including sustained activation of the sympathetic nervous system and reduced heart rate variability. Finally, we report research emphasizing the potential protective role of positive psychological constructs such as well-being, optimism, and positive affect.

Sympathoactivation is a prominent feature of heart failure (HF). Its role in cardiac remodeling and arrhythmogenesis is well-recognized today, although incomplete understanding of autonomic mechanisms was a barrier to development of contemporary medical therapies. Despite widespread availability of drugs and devices, mortality and morbidity in HF remain unacceptably high. Recognition of an additional phenotype, HF with preserved ejection fraction (EF), poses additional challenges. New treatment options are required. Electrical modulation of the central nervous system with baroreflex activation therapy offers a new approach. Activation of this afferent pathway induces the central nervous system to rebalance autonomic modulation of the cardiovascular system. Results in animal models of HF demonstrating increased survival and beneficial cardiac remodeling recently led to a clinical feasibility study in HF with reduced EF wherein the clinical course of patients dramatically improved. Results in resistant hypertension patients further suggest potential for benefit in HF with preserved EF.

he review aims to discuss the role of nerve growth factor (NGF) as a potential novel biomarker in post-myocardial infarction (MI) and in heart failure (HF), with a specific focus on neural remodeling and sprouting processes occurring after tissue damage. Many experimental data show that MI induces nerve sprouting, leading to increased sympathetic outflow and higher risk of ventricular arrhythmias and sudden cardiac death. In this framework, cardiac and circulating NGF might be an indicator of the innervation process and neural remodeling: it dramatically increases after MI, while it declines along with advanced HF and ventricular dysfunction. The bimodal behavior of NGF in acute and chronic settings leads to the speculation that NGF modulation may be a pharmacological target for intervention in different stages of the ischemic heart disease. Specifically, a fascinating possibility is to support or to inhibit NGF receptors, in order to prevent negative cardiac remodeling after MI and consequent ventricular dysfunction.

BACKGROUND: Baroreflex activation therapy (BAT) exerts in severe heart failure sympathoinhibitory effects, improving clinical variables and reducing hospitalization rate. The current follow-up study was aimed at determining the long-term effects of BAT, assessing whether BAT in heart failure allows to restore physiological levels of sympathetic function. METHODS: Seven patients out of the 11 heart failure patients aged 66.5 ± 3 years (mean ± SEM) in New York Heart Association Class III with left ventricular ejection fraction 40% or less and impaired functional capacity recruited in the study survived at the final follow-up (43.5 ± 2.1 months). Measurements included muscle sympathetic nerve activity (MSNA, microneurography) and spontaneous baroreflex-MSNA sensitivity together with hospitalization rate, echocardiography, Minnesota score, New York Heart Association class and standard clinical data. Measurements were collected before and at 6, 21 and 43 months following BAT. Data were compared with those collected in 17 age-matched healthy controls. All assessments were made with the heart failure patient on optimal active therapy. RESULTS: In the seven patients, BAT maintained its beneficial effects over 43.5 ± 2.1 months of follow-up. MSNA values underwent a progressive significant reduction from baseline to 21 and 43 months follow-up following BAT (from 46.2 ± 2.4 to 31.3 ± 3.0 e 26.6 ± 2.0 bursts/min, P < 0.05 at least), becoming almost superimposable to the ones seen in healthy controls (25.5 ± 0.8 bursts/min). Baroreflex-MSNA sensitivity improved, without achieving, however, a full normalization. Blood pressure and heart rate did not change. Left ventricular ejection fraction improved significantly from 32.3 ± 2 to 36.7 ± 3% (P < 0.05). Hospitalization rate decreased substantially when measured as days/year/patients it decreased from 10.3 ± 2.5 preimplant to 1.01 ± 1.4 at the 43.5th month follow-up (P < 0.02). No side effects were reported in the long-term period.

Chronic diseases are the leading causes of morbidity and mortality in Europe, accounting for more than 2/3 of all death causes and 75 % of the healthcare costs. Heart failure is one of the most prominent, prevalent and complex chronic conditions and is accompanied with multiple other chronic diseases. The current approach to care has important shortcomings with respect to diagnosis, treatment and care processes. A critical aspect of this situation is that interaction between stakeholders is limited and chronic diseases are usually addressed in isolation. Health care in Western countries requires an innovative approach to address chronic diseases to provide sustainability of care and to limit the excessive costs that may threaten the current systems. The increasing prevalence of chronic diseases combined with their enormous economic impact and the increasing shortage of healthcare providers are among the most critical threats. Attempts to solve these problems have failed, and future limitations in financial resources will result in much lower quality of care. Thus, changing the approach to care for chronic diseases is of utmost social importance.

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF. Methods and results: MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables. Conclusions: Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Aims: Baroreflex activation therapy (BAT) has recently been shown to reduce muscle sympathetic nerve activity and hospitalization rate while improving clinical variables through 6 months of therapy in patients with heart failure and reduced ejection fraction (HFrEF). The objective of the present study is to extend the information on this patient cohort over a long-term follow-up. Methods and results: Eleven patients were enrolled in the study and presented with optimized, stable medical therapy, New York Heart Association Class III HFrEF with left ventricular ejection fraction 40% or less, impaired functional capacity and no active cardiac resynchronization therapy. For the present report, muscle sympathetic nerve activity, baroreflex sensitivity data and hospitalization rate together with standard clinical data were collected at 12 and 21.5±4.2 months following BAT activation. Two patients died during long-term follow-up. The remaining nine patients maintained the improvements observed at 6 months, including reduced sympathetic activity and rates of hospitalization. Conclusion: BAT provides long-term chronic reductions in sympathetic activity and utilization of hospital resources in patients with HFrEF. General clinical presentation, quality of life and functional capacity are likewise improved and maintained. The temporal association of BAT with sympathetic drive diminution and improvement in objective clinical measures suggests a cause-and-effect relationship that will be verified in future randomized controlled trials of outcome.

During the past 30 years, myocardial ischemia/reperfusion injury in rodents became one of the most commonly used model in cardiovascular research. Appropriate pain-prevention appears critical since it may influence the outcome and the results obtained with this model. However, there are no proper guidelines for pain management in rats undergoing thoracic surgery. Accordingly, we evaluated three analgesic regimens in cardiac ischemia/reperfusion injury. This study was strongly focused on 3R's ethic principles, in particular the principle of Reduction.

Diagnostic accuracy in FDG-PET imaging highly depends on the operating procedures. In this clinical study on dementia, we compared the diagnostic accuracy at a single-subject level of a) Clinical Scenarios, b) Standard FDG Images and c) Statistical Parametrical (SPM) Maps generated via a new optimized SPM procedure. We evaluated the added value of FDG-PET, either Standard FDG Images or SPM Maps, to Clinical Scenarios. In 88 patients with neurodegenerative diseases (Alzheimer's Disease-AD, Frontotemporal Lobar Degeneration-FTLD, Dementia with Lewy bodies-DLB and Mild Cognitive Impairment-MCI), 9 neuroimaging experts made a forced diagnostic decision on the basis of the evaluation of the three types of information. There was also the possibility of a decision of normality on the FDG-PET images. The clinical diagnosis confirmed at a long-term follow-up was used as the gold standard. SPM Maps showed higher sensitivity and specificity (96% and 84%), and better diagnostic positive (6.8) and negative (0.05) likelihood ratios compared to Clinical Scenarios and Standard FDG Images. SPM Maps increased diagnostic accuracy for differential diagnosis (AD vs. FTD; beta 1.414, p = 0.019). The AUC of the ROC curve was 0.67 for SPM Maps, 0.57 for Clinical Scenarios and 0.50 for Standard FDG Images. In the MCI group, SPM Maps showed the highest predictive prognostic value (mean LOC = 2.46), by identifying either normal brain metabolism (exclusionary role) or hypometabolic patterns typical of different neurodegenerative conditions

Objectives: The purpose of this study was to test the hypothesis that differences in autonomic responses might modify clinical severity in long QT syndrome type 1 (LQT1) patients, those with KCNQ1 mutations and reduced IKs, in whom the main arrhythmia trigger is sympathetic activation. Background: Some long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained. Methods: In a South African LQT1 founder population segregating KCNQ1-A341V, we correlated major cardiac events to resting heart rate (HR) and to baroreflex sensitivity (BRS) on and off beta-adrenergic blockers (BB). Results: In 56 mutation carriers (MCs), mean HR was lower among asymptomatic patients (p < 0.05). Among MCs with a QT interval corrected for heart rate ≤500 ms, those in the lower HR tertile were less likely to have suffered prior cardiac events (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.04 to 0.79, p < 0.02). The BRS was lower among asymptomatic than symptomatic MCs (11.8 ± 3.5 ms/mm Hg vs. 20.1 ± 10.9 ms/mm Hg, p < 0.05). A BRS in the lower tertile was associated with a lower probability of being symptomatic (OR 0.13, 95% CI 0.02 to 0.96, p < 0.05). A similar trend was observed during BB. The MCs in the lower tertile for both HR and BRS were less frequently symptomatic than MCs with different patterns (20% vs. 76%, p < 0.05). Subjects with either ADRA2C-Del322-325 or homozygous for ADRB1-R389, 2 polymorphisms predicting enhanced adrenergic response, were more likely to have BRS values above the upper tertile (45% vs. 8%, p < 0.05). Conclusions: Lower resting HR and "relatively low" BRS are protective factors in KCNQ1-A341V carriers. A plausible underlying mechanism is that blunted autonomic responses prevent rapid HR changes, arrhythmogenic when IKs is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological ri