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Enterobacteriaceae are the most frequent pathogens in the Intensive Care Unit. Due to their safety and activity, β-Lactams (BL) and carbapenems represented the most common strategy adopted against these germs. The increasing exposure to these molecules led to the development of several types of antimicrobial resistance as the expression of extended-spectrum β-lactamases (ESBLs) and carbapenemases. Great molecular variability exists among these enzymes, with significant clinical impact. To limit morbidity and mortality, old antibiotics were tested and represent viable alternatives for specific types of infections, or once the spectrum of susceptibility of each germ has been determined. Alongside, new molecules have been specifically designed but enzyme molecular variability prevents the existence of one single antibiotic which fits for all. Therefore, a quicker identification of the molecular identity of each germ, together with the knowledge of the activity spectrum of each antibiotic is crucial to tailor the therapy and make it effective.

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Vitamin D covers roles of paramount importance in the regulation of multiple physiological pathways of the organism. The metabolism of vitamin D involves kidney–liver crosstalk and requires an adequate function of these organs, where vitamin D is progressively turned into active forms. Vitamin D deficiency has been widely reported in patients living in the community, being prevalent among the most vulnerable subjects. It has been also documented in many critically ill patients upon admission to the intensive care unit. In this context, vitamin D deficiency may represent a risk factor for the development of life-threatening clinical conditions (e.g., infection and sepsis) and worse clinical outcomes. Several researchers have investigated the impact of vitamin D supplementation showing its feasibility, safety, and effectiveness, although conflicting results have put into question its real benefit in critically ill patients. The existing studies included heterogeneous critically ill populations and used slightly different protocols of vitamin D supplementation. For these reasons, pooling up the results is difficult and not conclusive. In this narrative review, we described vitamin D physiology and the pathophysiology of vitamin D depletion with a specific focus on critically ill patients with liver dysfunction, acute kidney injury, acute respiratory failure, and sepsis.

Background: Microvascular invasion (MVI) is a necessary step in the metastatic evolution of hepatocellular carcinoma liver tumors. Predicting the onset of MVI in the initial stages of the tumors could improve patient survival and the quality of life. In this study, the possibility of using radiomic features to predict the presence/absence of MVI was evaluated. Methods: Multiphase contrast-enhanced computed tomography (CECT) images were collected from 49 patients, and the radiomic features were extracted from the tumor region and the zone of transition. The most-relevant features were selected; the dataset was balanced, and the presence/absence of MVI was classified. The dataset was split into training and test sets in three ways using cross-validation: the first applied feature selection and dataset balancing outside cross-validation; the second applied dataset balancing outside and feature selection inside; the third applied the entire pipeline inside the cross-validation procedure. Results: The features from the tumor areas on CECT showed both the portal and the arterial phases to be the most predictive. The three pipelines showed receiver operating characteristic area under the curve (ROC AUC) scores of 0.89, 0.84, and 0.61, respectively. Conclusions: The results obtained confirmed the efficiency of multiphase CECT and the ZOT in detecting MVI. The results showed a significant difference in the performance of the three pipelines, highlighting that a non-rigorous pipeline design could lead to model performance and generalization capabilities that are too optimistic.

Our current understanding of synergistic muscle control is based on the analysis of muscle activities. Modules (synergies) in muscle coordination are extracted from electromyographic (EMG) signal envelopes. Each envelope indirectly reflects the neural drive received by a muscle; therefore, it carries information on the overall activity of the innervating motor neurons. However, it is not known whether the output of spinal motor neurons, whose number is orders of magnitude greater than the muscles they innervate, is organized in a low-dimensional fashion when performing complex tasks. Here, we hypothesized that motor neuron activities exhibit a synergistic organization in complex tasks and therefore that the common input to motor neurons results in a large dimensionality reduction in motor neuron outputs. To test this hypothesis, we factorized the output spike trains of motor neurons innervating 14 intrinsic and extrinsic hand muscles and analyzed the dimensionality of control when healthy individuals exerted isometric forces using seven grip types. We identified four motor neuron synergies, accounting for >70% of the variance of the activity of 54.1 ± 12.9 motor neurons, and we identified four functionally similar muscle synergies. However, motor neuron synergies better discriminated individual finger forces than muscle synergies and were more consistent with the expected role of muscles actuating each finger. Moreover, in a few cases, motor neurons innervating the same muscle were active in separate synergies. Our findings suggest a highly divergent net neural inputs to spinal motor neurons from spinal and supraspinal structures, contributing to the dimensionality reduction captured by muscle synergies. SIGNIFICANCE STATEMENT We addressed whether the output of spinal motor neurons innervating multiple hand muscles could be accounted for by a modular organization, i.e., synergies, previously described to account for the coordination of multiple muscles. We found that motor neuron synergies presented similar dimensionality (implying a >10-fold reduction in dimensionality) and structure as muscle synergies. Nonetheless, the synergistic behavior of subsets of motor neurons within a muscle was also observed. These results advance our understanding of how neuromuscular control arises from mapping descending inputs to muscle activation signals. We provide, for the first time, insights into the organization of neural inputs to spinal motor neurons which, to date, has been inferred through analysis of muscle synergies.

We conducted a proof of concept study where Anapnoguard endotracheal tubes and its control unit were used in 15 patients with COVID-19 acute respiratory distress syndrome. Anapnoguard system provides suction, venting, rinsing of subglottic space and controls cuff pressure detecting air leakage through the cuff. Alpha-amylase and pepsin levels, as oropharyngeal and gastric microaspiration markers, were assessed from 85 tracheal aspirates in the first 72 h after connection to the system. Oropharyngeal microaspiration occurred in 47 cases (55%). Episodes of gastric microaspiration were not detected. Patient positioning, either prone or supine, did not affect alpha-amylase and pepsin concentration in tracheal secretions. Ventilator-associated pneumonia (VAP) rate was 40%. The use of the AG system provided effective cuff pressure control and subglottic secretions drainage. Despite this, no reduction in the incidence of VAP has been demonstrated, compared to data reported in the current COVID-19 literature. The value of this new technology is worth of being evaluated for the prevention of ventilator-associated respiratory tract infections.

We propose a neuromorphic framework to process the activity of human spinal motor neurons for movement intention recognition. This framework is integrated in a non-invasive interface that decodes the activity of motor neurons innervating intrinsic and extrinsic hand muscles. One of the main limitations of current neural interfaces is that machine learning models cannot exploit the efficiency of the spike encoding operated by the nervous system. Spiking-based pattern recognition would detect the spatio-temporal sparse activity of a neuronal pool and lead to adaptive and compact implementations, eventually running locally in embedded systems. Emergent Spiking Neural Networks (SNN) have not yet been used for processing the activity of in-vivo human neurons. Here we developed a convolutional SNN to process a total of 467 spinal motor neurons whose activity was identified in 5 participants while executing 10 hand movements. The classification accuracy approached 0.95 ± 0.14 for both isometric and non-isometric contractions. These results show for the first time the potential of highly accurate motion intent detection by combining non-invasive neural interfaces and SNN.

Introduction:This study presents the incidence of gastrointestinal stromal tumors (GISTs) in an Italian region of over 4 million inhabitants monitored for 10 years and is the largest incidence study of this type of cancer conducted so far in Italy.Methods:In order to ensure the registration of all GISTs, including those with nonmalignant behavior, a cancer list was integrated with the cases found through an ad hoc data mining process that covered all the pathologic reports of Puglia. Case distributions by sex, age groups, site, and prognostic groups according to Miettinem and Lasota classification and crude and age-standardized incidence rates were produced.Results:In the 10-year period 2006 to 2015, 708 cases of GIST were recorded in Puglia. The average crude incidence rate was 1.7 per 100,000 person-years and the age-standardized incidence rate, using 2013 European standard population, was 1.8 per 100,000 person-years (95% confidence interval [CI], 1.6–1.9). Incidence was higher in men than in women: crude incidence rate was 2.0 per 100,000 person-years and age-standardized incidence rate 2.2 per 100,000 person-years (95% CI, 2.0–2.4) in men and 1.5 per 100,000 person-years and 1.4 per 100,000 person-years (95% CI, 1.2–1.6) in women.Discussion:Our incidence rates are comparable with those of other international studies and they are located in the medium to high end of the range. The comparisons are affected by a different capacity of the cancer registries to intercept and record GISTs with nonmalignant behavior. Distribution of cases for sex, age groups, sites, and prognostic risk groups are consistent with previous results.

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the ‘real life’ clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32–57]. At VAP diagnosis, the median PaO2/FiO2 was 120 [100–164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75–14] vs. 7 [4–13] days, OR (95% CI): 1.069 (1.003–1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies.

Background Use of high positive end-expiratory pressure (PEEP) and prone positioning is common in patients with COVID-19-induced acute respiratory failure. Few data clarify the hemodynamic effects of these interventions in this specific condition. We performed a physiologic study to assess the hemodynamic effects of PEEP and prone position during COVID-19 respiratory failure. Methods Nine adult patients mechanically ventilated due to COVID-19 infection and fulfilling moderate-to-severe ARDS criteria were studied. Respiratory mechanics, gas exchange, cardiac output, oxygen consumption, systemic and pulmonary pressures were recorded through pulmonary arterial catheterization at PEEP of 15 and 5 cmH2O, and after prone positioning. Recruitability was assessed through the recruitment-to-inflation ratio. Results High PEEP improved PaO2/FiO2 ratio in all patients (p = 0.004), and significantly decreased pulmonary shunt fraction (p = 0.012), regardless of lung recruitability. PEEP-induced increases in PaO2/FiO2 changes were strictly correlated with shunt fraction reduction (rho=-0.82, p = 0.01). From low to high PEEP, cardiac output decreased by 18 % (p = 0.05) and central venous pressure increased by 17 % (p = 0.015). As compared to supine position with low PEEP, prone positioning significantly decreased pulmonary shunt fraction (p = 0.03), increased PaO2/FiO2 (p = 0.03) and mixed venous oxygen saturation (p = 0.016), without affecting cardiac output. PaO2/FiO2 was improved by prone position also when compared to high PEEP (p = 0.03). Conclusions In patients with moderate-to-severe ARDS due to COVID-19, PEEP and prone position improve arterial oxygenation. Changes in cardiac output contribute to the effects of PEEP but not of prone position, which appears the most effective intervention to improve oxygenation with no hemodynamic side effects.

As pesquisas mostram a pouca representatividade das mulheres na Computação, tanto nas instituições de ensino quanto nas organizações. Há trabalhos que relatam sobre a necessidade de criação de abordagens para aumentar o interesse das meninas pela área, assim como a divulgação de programas que auxiliem na construção da confiança delas. Estudos evidenciam a necessidade de mais ações e estratégias para reverter essa situação. Esta pesquisa relata a construção e a avaliação de um protótipo de um jogo direcionado a jovens mulheres com o intuito de incentivar o seu interesse pela Computação. Para isso, um questionário on-line foi disponibilizado para a coleta de requisitos, um protótipo foi desenvolvido e uma entrevista semiestruturada foi conduzida após a interação de meninas com esse protótipo. A partir dos resultados encontrados, foram relacionadas recomendações para jogos que atendam ao público em estudo, tais como, "o jogo deve ter humor", "o jogo deve informar sobre histórias reais de mulheres da Computação" e "o jogo deve permitir a customização dos avatares". Essas recomendações podem auxiliar a indústria de jogos no desenvolvimento de jogos digitais que incentivem as mulheres a se interessarem por jogos e pela Computação, diminuindo assim a lacuna existente.

Parkin plays an important role in ensuring efficient mitochondrial function and calcium homeostasis. Parkin-mutant human fibroblasts, with defective oxidative phosphorylation activity, showed high basal cAMP level likely ascribed to increased activity/expression of soluble adenylyl cyclase and/or low expression/activity of the phosphodiesterase isoform 4 and to a higher Ca2+ level. Overall, these findings support the existence, in parkin-mutant fibroblasts, of an abnormal Ca2+ and cAMP homeostasis in mitochondria. In our previous studies resveratrol treatment of parkin-mutant fibroblasts induced a partial rescue of mitochondrial functions associated with stimulation of the AMPK/SIRT1/PGC-1α pathway. In this study we provide additional evidence of the potential beneficial effects of resveratrol inducing an increase in the pre-existing high Ca2+ level and remodulation of the cAMP homeostasis in parkin-mutant fibroblasts. Consistently, we report in these fibroblasts higher expression of proteins implicated in the tethering of ER and mitochondrial contact sites along with their renormalization after resveratrol treatment. On this basis we hypothesize that resveratrol-mediated enhancement of the Ca2+ level, fine-tuned by the ER–mitochondria Ca2+ crosstalk, might modulate the pAMPK/AMPK pathway in parkin-mutant fibroblasts.

The recent fast development of virtual reality and robotic assistive devices enables to augment the capabilities of able-body individuals as well as to overcome the motor missing functions of neurologically impaired or amputee individuals. To control these devices, movement intentions can be captured from biological structures involved in the process of motor planning and execution, such as the central nervous system (CNS), the peripheral nervous system (in particular the spinal motor neurons) and the musculoskeletal system. Thus, human-machine interfaces (HMI) enable to transfer neural information from the neuro-muscular system to machines. To prevent any risks due to surgical operations or tissue damage in implementing these HMIs, a non-invasive approach is proposed in this thesis. In the last five decades, surface electromyography (sEMG) has been extensively explored as a non-invasive source of neural information. EMG signals are constituted by the mixed electrical activity of several recruited motor units, the fundamental components of muscle contraction. High-density sEMG (HD-sEMG) with the use of blind source separation methods enabled to identify the discharge patterns of many of these active motor units. From these decomposed discharge patterns, the net common synaptic input (CSI) to the corresponding spinal motor neurons was quantified with cross-correlation in the time and frequency domain or with principal component analysis (PCA) on one or few muscles. It has been hypothesised that this CSI would result from the contribution of spinal descending commands sent by supra-spinal structures and afferences integrated by spinal interneurons. Another motor strategy implying the integration of descending commands at the spinal level is the one regarding the coordination of many muscles to control a large number of articular joints. This neurophysiological mechanism was investigated by measuring a single EMG amplitude per muscle, thus without the use of HD-sEMG and decomposition. In this case, the aim was to understand how the central nervous system (CNS) could control a large set of muscles actuating a vast set of combinations of degrees of freedom in a modular way. Thus, time-invariant patterns of muscle coordination, i.e. muscle synergies , were found in animals and humans from EMG amplitude of many muscles, modulated by time-varying commands to be combined to fulfil complex movements. In this thesis, for the first time, we present a non-invasive framework for human-machine interfaces based on both spinal motor neuron recruitment strategy and muscle synergistic control for unifying the understanding of these two motor control strategies and producing control signals correlated to biomechanical quantities. This implies recording both from many muscles and using HD-sEMG for each muscle. We investigated 14 muscles of the hand, 6 extrinsic and 8 intrinsic. The first two studies, (in Chapters 2 and 3, respectively) present the framework for CSI quantification by PCA and the extraction of the synergistic organisation of spinal motor neurons innervating the 14 investigated muscles. For the latter analysis, in Chapter 3, we proposed the existence of what we named as motor neuron synergies extracted with non-negative matrix factorisation (NMF) from the identified motor neurons. In these first two studies, we considered 7 subjects and 7 grip types involving differently all the four fingers in opposition with the thumb. In the first study, we found that the variance explained by the CSI among all motor neuron spike trains was (53.0 ± 10.9) % and its cross-correlation with force was 0.67 ± 0.10, remarkably high with respect to previous findings. In the second study, 4 motor neuron synergies were identified and associated with the actuation of one finger in opposition with the thumb, finding even higher correlation values with force (over 0.8) for each synergy associated with a finger during the actuation of the relative finger. In Chapter 4, we then extended the set of analysed movements in a vast repertoire of gestures and repeated the analysis of Chapter 3 by finding a different synergistic organisation during the execution of tens of tasks. We divided the contribution among extrinsic and intrinsic muscles and we found that intrinsic better enable single-finger spatial discrimination, while no difference was found in regression of joint angles by dividing the two groups of muscles. Finally, in Chapter 5 we proposed the techniques of the previous chapters for cases of impairment due both to amputation and stroke. We analysed one case of pre and post rehabilitation sessions of a trans-humeral amputee, the case of a post-stroke trans-radial amputee and three cases of acute stroke, i.e. less than one month from the stroke event. We present future perspectives (Chapter 6) aimed to design and implement a platform for both rehabilitation monitoring and myoelectric control. Thus, this thesis provides a bridge between two extensively studied motor control mechanisms, i.e. motor neuron recruitment and muscle synergies, and proposes this framework as suitable for rehabilitation monitoring and control of assistive devices. Open Access

Orientador: Celso Pascoli Bottura Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação Resumo: Aprendizado por reforço e programação dinâmica aproximada são paradigmas para o aprendizado de controle ótimo. Um algoritmo on-line de iteração de política, em que é possível obter políticas de controle quase-ótimas sem que haja conhecimento a priori do modelo da dinâmica do sistema controlado é proposto. Nele, as melhorias de política devem ser realizadas a cada poucas transições de estado, usando somente uma avaliação incompleta da política atual. Para a etapa de avaliação de política é proposto o uso de máquinas kernel como aproximador da função valor com o objetivo de melhorar a capacidade de generalização dos algoritmos de predição de valor. Para esta etapa, são propostos dois algoritmos: o primeiro usa uma versão on-line da máquina de vetores suporte para regressão para aproximar a função valor no algoritmo de diferença temporal. O segundo algoritmo usa funções kernel Mercer para aproximar a função valor no algoritmo de diferença temporal por mínimos quadrados recursivo. Um procedimento de esparsificação com base na dependência linear aproximada das amostras é realizado para manter a esparsidade da solução. Para demonstrar a eficácia dos algoritmos propostos, os comparamos com outros algoritmos de aprendizado por reforço em problemas simples de controle não linear Abstract: Reinforcement learning and approximate dynamic programming are paradigms for optimal control learning. An online policy iteration algorithm, where near-optimal control policies can be obtained whithout a priori knowledge of the controlled system dynamic model is proposed. For this algorithm, policy improvements must be performed once every few state transitions, using only an incomplete evaluation of the current policy. For the policy evaluation step, the use of kernel machines as a value function approximator to improve the generalization ability of value prediction algorithms is proposed. For this step, two algorithms are proposed: the first one uses an online version of support vector regression to approximate the value function in the temporal difference algorithm. The second algorithm uses kernel Mercer functions to approximate the value function in the recursive least-squares temporal difference algorithm. A sparsification procedure based on approximate linear dependency of the samples is performed to keep the sparsity of the solution. To demonstrate the effectiveness of the proposed algorithms, they are compared with other reinforcement learning algorithms in simple nonlinear control benchmark tasks Doutorado Automação Doutor em Engenharia Elétrica CAPES

Objectives This study sought to describe the clinical and pathological features of anomalous origin of a coronary artery (AOCA) in sudden cardiac death (SCD) victims. Background AOCA from the inappropriate sinus of Valsalva or from the pulmonary artery is increasingly diagnosed with current imaging techniques. AOCA is a possible cause of SCD. Methods We reviewed a database of 5,100 consecutive cases of SCD referred to our specialist cardiac pathology center between January 1994 and March 2017 and identified a subgroup of 30 cases (0.6%) with AOCA. All cases underwent detailed post-mortem evaluation including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. Results The mean age was 28 ± 16 years and 23 individuals were male (77%). In 8 cases (27%), SCD occurred before 18 years of age. Cardiac symptoms were present in 11 individuals (37%), and syncope was the most common (n = 6, 20%). Anomalous left coronary artery arising from the right sinus of Valsalva (ALCA) with interarterial course (n = 11) and anomalous right coronary artery arising from the left sinus of Valsalva (ARCA) with interarterial course (n = 11) were the most common found. ALCA arising from pulmonary artery was present in 7 cases, whereas in 1 case, the left coronary artery arose from the noncoronary cusp. Left ventricular fibrosis was reported in 11 cases (37%) and was mainly subendocardial. There was evidence of acute infarction in 2 cases. Death occurred during exercise or emotional stress in 15 (50%) cases. The AOCA variant where death occurred more frequently during physical activity was ALCA (8 of 11, 73%), followed by ALCA arising from pulmonary artery (4 of 7, 57%) and ARCA (2 of 11, 18%). Conclusions AOCA is a rare cause of SCD. ALCA and ARCA with interarterial course are the most common anatomical variants recognized at the postmortem of SCD victims. ALCA is more commonly associated with death during exercise. Cardiac arrhythmias causing sudden death seem most likely in the cases without overt myocardial damage.

Background Hospitalized patients with COVID-19 admitted to the intensive care unit (ICU) and requiring mechanical ventilation are at risk of ventilator-associated bacterial infections secondary to SARS-CoV-2 infection. Our study aimed to investigate clinical features of Staphylococcus aureus ventilator-associated pneumonia (SA-VAP) and, if bronchoalveolar lavage samples were available, lung bacterial community features in ICU patients with or without COVID-19. Methods We prospectively included hospitalized patients with COVID-19 across two medical ICUs of the Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy), who developed SA-VAP between 20 March 2020 and 30 October 2020 (thereafter referred to as cases). After 1:2 matching based on the simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score, cases were compared with SA-VAP patients without COVID-19 (controls). Clinical, microbiological, and lung microbiota data were analyzed. Results We studied two groups of patients (40 COVID-19 and 80 non-COVID-19). COVID-19 patients had a higher rate of late-onset (87.5% versus 63.8%; p = 0.01), methicillin-resistant (65.0% vs 27.5%; p p p = 0.12), clinical cure (p = 0.20) and microbiological eradication (p = 0.31). On multivariable logistic regression analysis, SAPS II and initial inappropriate antimicrobial therapy were independently associated with ICU mortality. Then, lung microbiota characterization in 10 COVID-19 and 16 non-COVID-19 patients revealed that the overall microbial community composition was significantly different between the patient groups (unweighted UniFrac distance, R2 0.15349; p p S. aureus (log2 fold change, 29.5), Streptococcus anginosus subspecies anginosus (log2 fold change, 24.9), and Olsenella (log2 fold change, 25.7) were significantly enriched in the COVID-19 group compared to the non–COVID-19 group of SA-VAP patients. Conclusions In our study population, COVID-19 seemed to significantly affect microbiological and clinical features of SA-VAP as well as to be associated with a peculiar lung microbiota composition.

Additional file 1. Figure S1: e-diagram.

Additional file 2. eTable S1: Characteristics of 48 study patients diagnosed with MRSA-VAP.

Patients with coronavirus disease 19 (COVID-19) admitted to the intensive care unit (ICU) often develop respiratory fungal infections. The most frequent diseases are the COVID-19 associated pulmonary aspergillosis (CAPA), COVID-19 associated pulmonary mucormycosis (CAPM) and the Pneumocystis jirovecii pneumonia (PCP), the latter mostly found in patients with both COVID-19 and underlying HIV infection. Furthermore, co-infections due to less common mold pathogens have been also described. Respiratory fungal infections in critically ill patients are promoted by multiple risk factors, including epithelial damage caused by COVID-19 infection, mechanical ventilation and immunosuppression, mainly induced by corticosteroids and immunomodulators. In COVID-19 patients, a correct discrimination between fungal colonization and infection is challenging, further hampered by sampling difficulties and by the low reliability of diagnostic approaches, frequently needing an integration of clinical, radiological and microbiological features. Several antifungal drugs are currently available, but the development of new molecules with reduced toxicity, less drug-interactions and potentially active on difficult to treat strains, is highly warranted. Finally, the role of prophylaxis in certain COVID-19 populations is still controversial and must be further investigated.

Background: Although widely applied, noninvasive ventilatory support (NIVS) efficacy in COVID-19 disease is unknown. Early identification of treatment failure is warranted to avoid delays in endotracheal intubation and protective ventilation. We conducted a study to determine the rate of and factors associated to NIVS failure in critically ill patients with COVID-19 disease, and to compare NIVS failure rate in COVID-19 patients to that of a matched cohort with hypoxemic respiratory failure of other origins. Methods: All consecutive patients receiving first-line treatment NIVS for hypoxemic respiratory failure due to COVID-19 in the ICU of a University Hospital in Italy up to April 20th, 2020, were studied: laboratory data were collected on arrival, 28-day outcome was recorded. After one-to-one propensity score matching based on simplified acute physiology (SAPS) II score, age, PaO2/FiO2 and PaCO2 at arrival, NIVS failure rate in COVID-19 patients was compared to a previously published cohort who received NIVS during hypoxemic respiratory failure from other causes. Results: Eighty-five patients received first-line treatment with NIVS, mainly with helmet noninvasive ventilation and high-flow nasal cannula. Fifty-two patients (61%) needed endotracheal intubation. Independent predictors of NIVS failure were SAPSII score (adjusted hazard ratio 1.039 [1.018-1.061], Conclusions: COVID-19 patients receiving first-line NIVS are burdened by high risk of needing endotracheal intubation: this appears greater than that of patients affected by hypoxemic respiratory failure of other origins. In order to not delay endotracheal intubation, if logistically sustainable, NIVS use in the intensive care unit should be avoided in severe patients (SAPSII score≥33) with serum lactate de-hydrogenase≥405 Units/Liter.

Additional file 1 : Supplementary Table 1. Individual data of studied patients.

The administration of inhalation therapy is a basic treatment option for patients with many respiratory tract diseases, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Due to the exacerbations from which they often suffer, many of these patients also need non-invasive mechanical ventilation (NIV). Therefore, efforts have been made in recent years to put together both these therapies, on the assumption that the combined actions of both treatments can explicate a synergistic effect. The aim of this review is to discuss the most recent medical literature on the administration of inhalation therapy and on humidification during NIV.

Objectives: This study sought to describe the clinical and pathological features of anomalous origin of a coronary artery (AOCA) in sudden cardiac death (SCD) victims. Background: AOCA from the inappropriate sinus of Valsalva or from the pulmonary artery is increasingly diagnosed with current imaging techniques. AOCA is a possible cause of SCD. Methods: We reviewed a database of 5,100 consecutive cases of SCD referred to our specialist cardiac pathology center between January 1994 and March 2017 and identified a subgroup of 30 cases (0.6%) with AOCA. All cases underwent detailed post-mortem evaluation including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. Results: The mean age was 28 ± 16 years and 23 individuals were male (77%). In 8 cases (27%), SCD occurred before 18 years of age. Cardiac symptoms were present in 11 individuals (37%), and syncope was the most common (n = 6, 20%). Anomalous left coronary artery arising from the right sinus of Valsalva (ALCA) with interarterial course (n = 11) and anomalous right coronary artery arising from the left sinus of Valsalva (ARCA) with interarterial course (n = 11) were the most common found. ALCA arising from pulmonary artery was present in 7 cases, whereas in 1 case, the left coronary artery arose from the noncoronary cusp. Left ventricular fibrosis was reported in 11 cases (37%) and was mainly subendocardial. There was evidence of acute infarction in 2 cases. Death occurred during exercise or emotional stress in 15 (50%) cases. The AOCA variant where death occurred more frequently during physical activity was ALCA (8 of 11, 73%), followed by ALCA arising from pulmonary artery (4 of 7, 57%) and ARCA (2 of 11, 18%). Conclusions: AOCA is a rare cause of SCD. ALCA and ARCA with interarterial course are the most common anatomical variants recognized at the postmortem of SCD victims. ALCA is more commonly associated with death during exercise. Cardiac arrhythmias causing sudden death seem most likely in the cases without overt myocardial damage.

The Cancer Registry of Puglia (RTP) was instituted in 2008 as a regional population-based cancer registry. It consists of six sections (Foggia, Barletta-Andria-Tran, Bari, Brindisi, Lecce, and Taranto) and covers more than 4 000 000 inhabitants. At present, four of six sections have received accreditation by AIRTUM (53% of regional population). To point out possible regional geographic variability in cancer incidence and also to support health services planning, we developed an original estimation method to ensure a complete territorial coverage. Incidence data of the four accredited RTP sections for the shared incidence period 2006–2008, the 2001–2009 hospitalization regional data, and 2006–2009 mortality data were considered. To take into account specific health features of different provinces, we performed an estimate of cancer incidence rates of nonaccredited sections using a combination of accredited sections rates and a factor that combines mortality and hospitalization ratios available for all the sections. Finally, we validated the method and we applied it to estimate regional cancer rates as the population-weighted average of accredited sections and nonaccredited sections adjusted rates. The validation process shows that estimated rates are close to real incidence data. The most frequent neoplasms in Apulia are breast (direct standardized rates 96.8 per 100 000 inhabitants), colon–rectum (36.6), and thyroid cancer (25.3) in women and prostate (70.2), lung (68.4), and colon–rectum cancer (52.2) in men. This method could be useful to assess the cancer incidence when complete cancer registration data are not available, but hospitalization, mortality, and neighbouring incidence data are available.

Rationale: High-flow nasal cannula (HFNC) and helmet noninvasive ventilation (NIV) are used for the management of acute hypoxemic respiratory failure.Objectives: Physiological comparison of HFNC an...

to estimate the environmental and health impact attributable to PM2.5 emissions from the ex-ILVA steel plant in Taranto and the ENEL power plant in Brindisi (Apulia Region, Southern Italy).a SPRAY Lagrangian dispersion model was used to estimate PM2.5 concentrations and population weighted exposures following the requirements of the Integrated Environmental Authorization (IEA) of the two plants under study. Available concentration-response functions (OMS/HRAPIE and updates) were used to estimate the number of attributable premature deaths.residents in the 40 municipalities of the domains of the VDS (assessment of health damage, according to the Regional Law n. 21/2012) of Brindisi (source: Italian National Institute of Statistics 2011 Census) and residents in Taranto, Statte, and Massafra (source: cohort study).mortality from natural causes, cardiovascular and respiratory diseases, and lung cancer attributable to PM2.5. Incremental lifetime cumulative risks (ILCRs) for lung cancer associated to PM2.5 exposure.there was a reduction of the estimated impacts from the pre to the post IEA-scenarios in both Taranto and Brindisi. In Taranto, ILCRs greater than 1x10the Integrated Environmental Health Impact Assessment confirmed the results of the VDS conducted according to the toxicological risk assessment approach. An unacceptable risk was estimated for Tamburi also for the 2015 scenario, characterized by a production of 4.7 million tons of steel, about half compared to one foreseen by the IEA (8 mt.).

We propose a framework based on high-density surface electromyography (HD-sEMG) to identify the neural drive to muscles controlling the human hand. High-density (320 channels) sEMG signals were recorded concurrently from intrinsic (the four dorsal interossei and thenar) and extrinsic (forearm) hand muscles and then decomposed into the constituent trains of motor unit (MU) action potentials. The participants performed pinch tasks with simultaneous activation of the thumb and one of the other fingers with sinusoidal force variations. The common drive among MUs across different muscles was extracted via principal component analysis (PCA) of the smoothed MU discharge rates. The first principal component of the smoothed discharge rates of all identified motor neurons explained 48.7 ± 15.4% of the total variance across all pinching tasks, indicating a common neural input shared by different muscles of the forearm and the hand.. When considering only the MUs extracted from extrinsic and intrinsic muscles, the percent of variance explained was 48.3 ± 15.3% and 57.1 ± 15.5%, respectively. This framework is conceived to use motor neuron activity for a proportional myoelectric control and rehabilitation technologies. A wearable adaptation of the framework is proposed for future perspectives.

The evaluation of the spatial representativeness of air quality monitoring stations is of fundamental relevance when observed concentration levels are used in air quality assessment. Since no reference method is provided, there is a need to develop tools for its quantitative assessment. In this paper we test a recently developed methodology for spatial representativeness area assessment, based on the analysis of time series of model concentrations by means of a Concentration Similarity Frequency (CSF) function, on the Taranto-via Machiavelli industrial monitoring station, located in a mid-size city in Southern Italy. The complex territorial context, the peculiar anthropogenic emissions features, dominated by the contribution of the largest steelworks in Europe, and the critical situation of human health in the city make this application an interesting case study to assess the portability of the CSF approach, so far applied only to background stations, to industrial sites that experience high concentration variability. A comprehensive characterization of the main anthropogenic emissions of the area was carried out, with detailed treatment of dust emission by wind erosion from industrial mineral piles; a Lagrangian modelling approach was chosen to simulate PM10 dispersion patterns, to achieve a reliable and high resolution description of concentration variability around the site. The resulting representativeness area of the station is 0.067 km2, fulfilling EU prescriptions for industrial stations. The comprehensive evaluation results, through the comparison with the observed data, showed good performances pointing out the reliability of the estimated concentration fields around the site and consequently of the assessment of its representativeness area.

The monitoring of quality parameters in horticultural crops under artificial light during postharvest storage is important for controlling the shelf-life of the crops. In this work, white light, red light, blue light and dark conditions were used at various durations to evaluate the effects of different spectral properties of light on parameters related to physiological and biochemical processes in green asparagus, and on compounds related to human health. For this aim, the level of glucose, fructose and sucrose, as well as that of vitamin C and the levels of lignin, chlorophyll a and b, carotenoids and anthocyanins, were determined in apical and basal segments of the edible portion of green asparagus spears before and after light treatments. A dark control was stored at 4 °C. The irradiance levels of the light treatments were 100, 117 and 116 μmol m−2 s−1, respectively for white, blue and red light. Before treatments, in the apical segments, the content of analysed components were higher than in the basal segments, except for soluble sugars and starch, of which the basal segment exhibited higher levels; these results exhibited different nutritional value of the two segments. After the light treatments, the analysed quality-related parameters were differently influenced in the apical and basal segments during postharvest storage. The increase in dry matter content in the apical segment after both white light and red light treatments was most likely attributable to the presence of physiological postharvest activity, rather than to increased transpiration. The results indicated that light with different spectral properties vs. dark-stored controls had small or no effects on the measured parameters. Both light and dark caused the starch levels to increase in both segments. A decrease in the sugar content in the basal part might be explained by translocation of hexoses from basal towards apical regions of the spear. White light primarily determined the lignin deposition in the apical part most likely due to the synergistic effect of red and blue light on lignin biosynthesis. The vitamin C, chlorophyll a and b and carotenoids decreased in light and dark treatments in both segments. Anthocyanins were induced by light in the basal part only, most so by blue light.

Purpose – Though the very high prevalence of psychiatric disorders (PD) in people with intellectual disability (PwID), the impact of these disorders on adaptive functioning has been minimally investigated. The few contributions present in the literature focussed on children, adolescents, and individual with autism spectrum disorders (ASD). There are no studies concerning the evaluation of any kind of impact on individual skills. Comparison studies between PD and organic disorders, including neurological disorders (ND), was also underexplored. The purpose of this paper is to assess the impact of the presence of a PD on the adaptive functioning of adults with intellectual disability (ID). Design/methodology/approach – In total, 107 adults with ID living in residential facilities or attending day care centers in Tuscany were consecutively assessed with the Psychiatric Instrument for the Intellectually Disabled Adult (SPAID-G), the Diagnostic Manual-Intellectual Disability (DM-ID) criteria, and the Vineland Adaptive Behavior Scales (VABS). The scores were statistically compared and results were controlled for level of ID and other background variables. Findings – The presence of a PD resulted to have a significant negative impact on individual adaptive skills. Participants with PD scored significantly lower than those without PD in communication and socialization areas of VABS. Participants with ND scored significantly lower than people without ND in daily living and motor skills. The average scores of participants with only PD and those of participants with PD and ND showed no significant differences. Significant differences were found between participants with only ND and participants with ND and PD in the interpersonal relationship subscale. Originality/value – As far as the best knowledge, this is the first study on the evaluation of the impact of any kind of PD on the abilities of PwID. This paper suggests that the presence of a PD seems to have a relevant negative impact on functioning of PwID higher than that of ND, particularly in communication and socialization skills.

Objective. We present a non-invasive framework for investigating efferent commands to 14 extrinsic and intrinsic hand muscles. We extend previous studies (limited to a few muscles) on common synaptic input among pools of motor neurons in a large number of muscles. Approach. Seven subjects performed sinusoidal isometric contractions to complete seven types of grasps, with each finger and with three combinations of fingers in opposition with the thumb. High-density surface EMG (HD-sEMG) signals (384 channels in total) recorded from the 14 muscles were decomposed into the constituent motor unit action potentials. This provided a non-invasive framework for the investigation of motor neuron discharge patterns, muscle coordination and efferent commands of the hand muscles during grasping. Moreover, during grasping tasks, it was possible to identify common neural information among pools of motor neurons innervating the investigated muscles. For this purpose, principal component analysis (PCA) was applied to the smoothed discharge rates of the decoded motor units. Main results. We found that the first principal component (PC1) of the ensemble of decoded motor neuron spike trains explained a variance of (53.0 ± 10.9) % and was positively correlated with force (R = 0.67 ± 0.10 across all subjects and tasks). By grouping the pools of motor neurons from extrinsic or intrinsic muscles, the PC1 explained a proportion of variance of (57.1 ± 11.3) % and (56.9 ± 11.8) %, respectively, and was correlated with force with R = 0.63 ± 0.13 and 0.63 ± 0.13, respectively. Significance. These observations demonstrate a low dimensional control of motor neurons across multiple muscles that can be exploited for extracting control signals in neural interfacing. The proposed framework was designed for hand rehabilitation perspectives, such as post-stroke rehabilitation and hand-exoskeleton control.

The aim of the SCINTIRAD experiment is to determine the radio-response of 188Rhenium (Re) in in vitro cells and the biodistribution in different organs of in vivo mice, and subsequently to assess the therapeutic effect on liver tumours induced in mice. Both the γ- and β- emissions of 188Re have been exploited in the experiment. The in vivo biodistribution in mice was studied also with a γ-camera using different parallel hole collimators. In the 188Re spectrum, while the 155 keV γ-peak is useful for imaging, the photons emitted at larger energies and the β-particles act as noise in the image reconstruction. The γ-cameras previously used to image biodistributions obtained with 99Tc are, therefore, not optimized for use with 188Re. A new setup of the γ-camera has been studied for 188Re: 66×66 YAP:Ce crystals (0.6×0.6×10 mm3, 5 μm optical insulation) guarantee a FOV of 40×40 mm2, a Hamamatsu R2486 PSPMT, 3 in. diameter, converts their light into an electrical signal and allows reconstructing the spatial coordinates of the light spot; incoming photon directions are selected through a lead collimator with 1.5 mm diameter hexagonal holes, 0.18 mm septa, 40 mm thickness. Using this setup, results have been obtained both with 99Tc filled and 188Re filled capillaries and wells. The energy spectrum of the collected photons and the spatial resolutions obtainable with the 188Re source will be presented.

Background: A large steel plant close to the urban area of Taranto (Italy) has been operating since the sixties. Several studies conducted in the past reported an excess of mortality and morbidity from various diseases at the town level, possibly due to air pollution from the plant. However, the relationship between air pollutants emitted from the industry and adverse health outcomes has been controversial. We applied a variant of the “difference-in-differences” (DID) approach to examine the relationship between temporal changes in exposure to industrial PM10 from the plant and changes in cause-specific mortality rates at area unit level. Methods: We examined a dynamic cohort of all subjects (321,356 individuals) resident in the Taranto area in 1998–2010 and followed them up for mortality till 2014. In this work, we included only deaths occurring on 2008–2014. We observed a total of 15,303 natural deaths in the cohort and age-specific annual death rates were computed for each area unit (11 areas in total). PM10 and NO2 concentrations measured at air quality monitoring stations and the results of a dispersion model were used to estimate annual average population weighted exposures to PM10 of industrial origin for each year, area unit and age class. Changes in exposures and in mortality were analyzed using Poisson regression. Results: We estimated an increased risk in natural mortality (1.86%, 95% confidence interval [CI]: −0.06, 3.83%) per 1 μg/m3 annual change of industrial PM10, mainly driven by respiratory causes (8.74%, 95% CI: 1.50, 16.51%). The associations were statistically significant only in the elderly (65+ years). Conclusions: The DID approach is intuitively simple and reduces confounding by design. Under the multiple assumptions of this approach, the study indicates an effect of industrial PM10 on natural mortality, especially in the elderly population. Keywords: Air pollution, Mortality, PM10, Steel industry, Confounding, Difference-in-differences

Background and aims Sudden cardiac death (SCD) is a relatively common cause of death in hypertrophic cardiomyopathy (HCM). HCM patients presenting at >60 years of age of life are considered at low risk for disease-related morbidity/mortality, including SCD. The aim of the study was to investigate the demographics of SCD in a large cohort of patients that died suddenly with a post-mortem diagnosis of HCM. Methods We reviewed a database of 5100 consecutive cases of SCDs referred to our specialist cardiac pathology centre between 1994 and March 2017 and identified 196 (4%) cases with HCM. Two groups were considered: Group 1 (SCD at 60 years of age) and Group 2 (SCD at >60 years of age). All cases underwent detailed post-mortem evaluation including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. Results Group 1 and Group 2 comprised of 176 (90%) and 20 (10%) individuals, respectively. Male gender was prevalent in Group 1 (n=134, 76%), but not in Group 2 (n=9, 45%), (p=0.007). Death occurred at rest in 130 (75%) individuals in Group 1 and in 17 (85%) individuals in Group 2. Previous cardiac symptoms were present in 46 (26%) individuals in Group 1 and in 5 (25%) individuals in Group 2, p=0.56. The mean heart weight was similar in the two groups (554±184 in Group 1 vs 593±209 in Group 2, p=0.38). Left ventricular (LV) fibrosis was present in 106 (60%) individuals in Group 1 and in 9 (45%) in Group 2, p=0.29. Associated critical coronary artery stenosis were found in 3 (3%) cases in Group 1 and in 2 (10%) cases in Group 2, p=0.47. Conclusions SCD in elderly patients with HCM is a rare but possible event. SCD victims with HCM who died at less than 60 years of age are predominantly males, whereas older patients are more frequently females. Cardiac symptoms and diagnosis prior to death are reported in 1 in 4 individuals suggesting that SCD is often the first manifestation of the disease.

Background and aims Anomalous origin of a coronary artery (AOCA) from the inappropriate sinus of Valsalva or from the pulmonary artery is increasingly diagnosed with current imaging techniques. Although most AOCA subtypes are benign, they can rarely cause sudden cardiac death (SCD). The aim of the study was to describe the clinical and pathological features of AOCA in SCD victims. Methods We reviewed a database of 5100 consecutive cases of SCDs referred to our specialist cardiac pathology centre between 1994 and March 2017 and identified a subgroup of 30 (0.6%) cases with AOCA. All cases underwent detailed post-mortem evaluation including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. Results The mean age was 28±16 years and 23 individuals were males (77%). In 8 (27%) cases SCD occurred before 18 years of age. Cardiac symptoms were present in 11 (37%) individuals and syncope was the most common (n=6, 20%). The mean heart weight was 367±115 g. The most common anomalies were anomalous left coronary artery arising from the right sinus of Valsalva (ALCA) with inter-arterial course (n=11) and anomalous right coronary artery arising from the left sinus of Valsalva (ARCA) with inter-arterial course (n=11). Anomalous left coronary artery arising from pulmonary artery (ALCAPA) was present in 7 cases, while in 1 case the LCA arose from the non-coronaric cusp. Death occurred during exercise in 14 (47%) cases. The AOCA variant where death occurred more frequently during physical activity was ALCA (7/11, 64%), followed by ALCAPA (4/7, 57%) and ARCA (2/11, 18%). Conclusions AOCA is a rare cause of SCD. Anomalous left or right coronary artery arising from the wrong sinus of Valsalva with inter-arterial course is the most common anatomical variant recognised at the post-mortem of SCD victims. While in ALCA death is commonly associated with exercise, in ARCA death occurs usually during rest or sleep.

The region of Apulia, which is located in the south-east tip of the Italian Peninsula, has a typical Mediterranean climate with mild winters and hot-dry summers. Agriculture, an important sector of its economy, is potentially threatened by future climate change. This study describes the evolution of seasonal temperature and precipitation from the recent past to the next decades and estimates future potential impacts of climate change on three main agricultural products: wine, wheat and olives. Analysis is based on instrumental data, on an ensemble of climate projections and on a linear regression model linking these three agricultural products to seasonal values of temperature and precipitation. In Apulia, precipitation and temperature time series show trends toward warmer and marginally drier conditions during the whole analyzed (1951–2005) period: 0.18 °C/decade in mean annual minimum temperature and −14.9 mm/decade in the annual total precipitation. Temperature trends have been progressively increasing and rates of change have become noticeably more intense during the last 25 years of the twentieth century. Model simulations are consistent with observed trends for the period 1951–2000 and show a large acceleration of the warming rate in the period 2001–2050 with respect to the period 1951–2000. Further, in the period 2001–2050, simulations show a decrease in precipitation, which was not present in the previous 50 years. Wine production, wheat and olive harvest records show large inter-annual variability with statistically significant links to seasonal temperature and precipitation, whose strength, however, strongly depends on the considered variables. Linear regression analysis shows that seasonal temperature and precipitation variability explains a small, but not negligible, fraction of the inter-annual variability of these crops (40, 18, 9 % for wine, olives and wheat, respectively). Results (which consider no adaptation of crops and no fertilization effect of CO2) suggest that evolution of these seasonal climate variables in the first half of the twenty-first century could decrease all considered variables. The most affected is wine production (−20 ÷ −26 %). The effect is relevant also on harvested olives (−8 ÷ −19 %) and negligible on harvested wheat (−4 ÷ −1 %).

The present investigation aimed to characterise the shape of dose-response curve and determining the frequency distribution of various aberration types as a function of dose and radiation quality in AG01522 primary human fibroblasts in the 0.1- to 1-Gy dose range. For this purpose, the cells were irradiated with 7.7 and 28.5 keV µm(-1) low-energy protons, 62 keV µm(-1 4)He(2+) ions (LNL Radiobiology facility) or X rays and samples collected for 24-colour mFISH analysis. X rays and 7.7 keV µm(-1) protons displayed a quadratic dose-response curve solely for total and simple exchanges, whereas for high-linear energy transfer radiations, a linear dose-response curve was observed for all the aberration categories, with the exception of complex exchanges.