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Abstract Background Colistin, administered as intravenous colistimethate (CMS), is still used in the critical care setting and current guidelines recommend high dosage CMS in patients undergoing continuous renal replacement therapy (CRRT). Due to the paucity of real-life data, we aimed to describe colistin pharmacokinetic/pharmacodynamic (PK/PD) profile in a cohort of critically ill patients with infections due to carbapenem-resistant (CR) bacteria undergoing CRRT. Results All consecutive patients admitted to three Intensive Care Units (ICUs) of a large metropolitan University Hospital, treated with colistin for at least 48 h at the dosage of 6.75 MUI q12, after 9 MIU loading dose, and undergoing CRRT were included. After the seventh dose, patients underwent blood serial sampling during a time frame of 24 h. We included 20 patients, who had CR-Acinetobacter baumannii ventilator-associated pneumonia and were characterized by a median SAPS II and SOFA score of 41 [34.5–59.3] and 9 [6.7–11], respectively. Fifteen patients died during ICU stay and six recovered renal function. Median peak and trough colistin concentrations were 16.6 mcg/mL [14.8–20.6] and 3.9 mcg/mL [3.3–4.4], respectively. Median area under the time–concentration curve (AUC0 − 24) and average steady-state concentration (Css, avg) were 193.9 mcg h/mL [170.6–208.6] and 8.07 mcg/mL [7.1–8.7]. Probability of target attainment of colistin pharmacodynamics according to the fAUC0 − 24/MIC target ≥ 12 was 100% for MIC ≤ 2 mcg/mL and 85% for MIC = 4 mcg/ML, although exceeding the toxicity limit of Css, avg 3–4 mcg/mL. Conclusions In critically ill patients with CR infections undergoing CRRT, recommended CMS dosage resulted in colistin plasmatic levels above bacterial MIC90, but exceeding the safety Css, avg. limit. Trial registration This trial was registered in ClinicalTrials.gov on 23/07/2021 with the ID NCT04995133 (https//clinicaltrials.gov/study/NCT04995133).

Abstract Severe infections frequently require admission to the intensive care unit and cause life-threatening complications in critically ill patients. In this setting, severe infections are acknowledged as prerequisites for the development of sepsis, whose pathophysiology implies a dysregulated host response to pathogens, leading to disability and mortality worldwide. Vitamin D is a secosteroid hormone that plays a pivotal role to maintain immune system homeostasis, which is of paramount importance to resolve infection and modulate the burden of sepsis. Specifically, vitamin D deficiency has been widely reported in critically ill patients and represents a risk factor for the development of severe infections, sepsis and worse clinical outcomes. Several studies have demonstrated the feasibility, safety and effectiveness of vitamin D supplementation strategies to improve vitamin D body content, but conflictual results support its benefit in general populations of critically ill patients. In contrast, small randomised clinical trials reported that vitamin D supplementation may improve host-defence to pathogen invasion via the production of cathelicidin and specific cytokines. Nonetheless, no large scale investigations have been designed to specifically assess the impact of vitamin D supplementation on the outcome of critically ill septic patients admitted to the intensive care unit.

ABSTRACTFew data are available on the lung microbiota composition of patients with coronavirus disease 2019-related acute respiratory distress syndrome (C-ARDS) receiving invasive mechanical ventilation (IMV). Moreover, it has never been investigated whether there is a potential correlation between lung microbiota communities and respiratory mechanics. We performed a prospective observational study in two intensive care units of a university hospital in Italy. Lung microbiota was investigated by bacterial 16S rRNA gene sequencing, performed on bronchoalveolar lavage fluid samples withdrawn after intubation. The lung bacterial communities were analyzed after stratification by respiratory system compliance/predicted body weight (Crs) and ventilatory ratio (VR). Weaning from IMV and hospital survival were assessed as secondary outcomes. In 70 C-ARDS patients requiring IMV from 1 April through 31 December 2020, the lung microbiota composition (phylum taxonomic level, permutational multivariate analysis of variance test) significantly differed between who had low Crs vs those with high Crs (P = 0.010), as well as in patients with low VR vs high VR (P = 0.012). As difference-driving taxa, Proteobacteria (P = 0.017) were more dominant and Firmicutes (P = 0.040) were less dominant in low- vs high-Crs patients. Similarly, Proteobacteria were more dominant in low- vs high-VR patients (P = 0.013). After multivariable regression analysis, we further observed lung microbiota diversity as a negative predictor of weaning from IMV and hospital survival (hazard ratio = 3.31; 95% confidence interval, 1.52–7.20, P = 0.048). C-ARDS patients with low Crs/low VR had a Proteobacteria-dominated lung microbiota. Whether patients with a more diverse lung bacterial community may have more chances to be weaned from IMV and discharged alive from the hospital warrants further large-scale investigations.IMPORTANCELung microbiota characteristics were demonstrated to predict ventilator-free days and weaning from mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). In this study, we observed that in severe coronavirus disease 2019 patients with ARDS who require invasive mechanical ventilation, lung microbiota characteristics were associated with respiratory mechanics. Specifically, the lung microbiota of patients with low respiratory system compliance and low ventilatory ratio was characterized by Proteobacteria dominance. Moreover, after multivariable regression analysis, we also found an association between patients’ microbiota diversity and a higher possibility of being weaned from mechanical ventilation and discharged alive from the hospital. For these reasons, lung microbiota characterization may help to stratify patient characteristics and orient the delivery of target interventions. (This study has been registered at ClinicalTrials.gov on 17 February 2020 under identifier NCT04271345.)Clinical TrialRegistered at ClinicalTrials.gov, 17 February 2020 (NCT0427135).

Abstract Background COVID-19 vaccination has been proved to be effective in preventing hospitalization and illness progression, even though data on mortality of vaccinated patients in the intensive care unit (ICU) are conflicting. The aim of this study was to investigate the characteristics of vaccinated patients admitted to ICU according to their immunization cycle and to outline the risk factors for 28-day mortality. This observational study included adult patients admitted to ICU for acute respiratory failure (ARF) due to SARS-CoV-2 and who had received at least one dose of vaccine. Results Fully vaccination was defined as a complete primary cycle from 14 days. All the other patients were named partially vaccinated. One-hundred sixty patients (91 fully and 69 partially vaccinated) resulted eligible, showing a 28-day mortality rate of 51.9%. Compared to partially vaccinated, fully vaccinated were younger (69 [60–77.5] vs. 74 [66–79] years, p 0.029), more frequently immunocompromised (39.56% vs. 14.39%, p 0.003), and affected by at least one comorbidity (90.11% vs 78.26%, p 0.045), mainly chronic kidney disease (CKD) (36.26% vs 20.29%, p 0.035). At multivariable analysis, independent predictors of 28-day mortality were as follows: older age [OR 1.05 (CI 95% 1.01–1.08), p 0.005], history of chronic obstructive pulmonary disease (COPD) [OR 3.05 (CI 95% 1.28–7.30), p 0.012], immunosuppression [OR 3.70 (CI 95% 1.63–8.40), p 0.002], and admission respiratory and hemodynamic status [PaO2/FiO2 and septic shock: OR 0.99 (CI 95% 0.98–0.99), p 0.009 and 2.74 (CI 95% 1.16–6.48), p 0.022, respectively]. Conclusions Despite a full vaccination cycle, severe COVID-19 may occur in patients with relevant comorbidities, especially immunosuppression and CKD. Regardless the immunization status, predisposing conditions (i.e., older age, COPD, and immunosuppression) and a severe clinical presentation were predictors of 28-day mortality.

IntroductionIn Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, associations have been reported between gender, environmental factors, and lung cancer mortality in women and men. The aim of this study was to investigate the relationships between gender, residence in areas with high environmental pressures, bronchus/lung cancer characteristics, and death rate.MethodsData from the Taranto Cancer Registry were used, including all women and men with invasive bronchus/lung cancer diagnosed between 1 January 2016 and 31 December 2020 and with follow-up to 31 December 2022. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics.ResultsA total of 2,535 person-years were observed. Male gender was associated with a higher prevalence of histological grade 3 (OR 2.45, 95% CrI 1.35–4.43) and lung squamous-cell carcinoma (OR 3.04, 95% CrI 1.97–4.69). Variables associated with higher death rate were male gender (HR 1.24, 95% CrI 1.07–1.43), pathological/clinical stage II (HR 2.49, 95% CrI 1.63–3.79), III (HR 3.40, 95% CrI 2.33–4.97), and IV (HR 8.21, 95% CrI 5.95–11.34), histological grade 3 (HR 1.80, 95% CrI 1.25–2.59), lung squamous-cell carcinoma (HR 1.18, 95% CrI 1.00–1.39), and small-cell lung cancer (HR 1.62, 95% CrI 1.31–1.99). Variables associated with lower death rate were other-type lung cancer (HR 0.65, 95% CrI 0.44–0.95), high immune checkpoint ligand expression (HR 0.75, 95% CrI 0.59–0.95), lung localization (HR 0.73, 95% CrI 0.62–0.86), and left localization (HR 0.85, 95% CrI 0.75–0.95).DiscussionThe results among patients with lung cancer did not show an association between residence in the contaminated site of national interest (SIN) and the prevalence of the above mentioned prognostic factors, nor between residence in SIN and death rate. The findings confirmed the independent prognostic values of different lung cancer characteristics. Even after adjusting for patients and disease characteristics, male gender appeared to be associated with a higher prevalence of poorly differentiated cancer and squamous-cell carcinoma, and with an increased death rate.

IntroductionIn Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, few associations have been reported between environmental factors and breast cancer mortality in women. The aim of this study was to investigate the relationships between residence in areas with high environmental pressures, female breast cancer characteristics, and death rate.MethodsData from the Taranto Cancer Registry were used, including all women with invasive breast cancer diagnosed between 01 January 2015 and 31 December 2020 and with follow-up to 31 December 2021. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics.ResultsA total of 10,445 person-years were observed. Variables associated with higher death rate were residence in the contaminated site of national interest (SIN) (HR 1.22, 95% CrI 1.01–1.48), pathological/clinical stage III (HR 2.77, 95% CrI 1.93–3.97) and IV (HR 17.05, 95% CrI 11.94–24.34), histological grade 3 (HR 2.50, 95% CrI 1.20–5.23), Ki-67 proliferation index of 21–50% (HR 1.42, 95% CrI 1.10–1.83) and > 50% (HR 1.81, 95% CrI 1.29–2.55), and bilateral localization (HR 1.65, 95% CrI 1.01–2.68). Variables associated with lower death rate were estrogen and/or progesterone receptor positivity (HR 0.61, 95% CrI 0.45–0.81) and HER2/neu oncogene positivity (HR 0.59, 95% CrI 0.44–0.79).DiscussionThe findings confirmed the independent prognostic values of different female breast cancer characteristics. Even after adjusting for patients and disease characteristics, residence in the SIN of Taranto appeared to be associated with an increased death rate.

Abstract Background Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. Methods In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. Results Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide

Antimicrobial de-escalation (ADE) is defined as the discontinuation of one or more antimicrobials in empirical therapy, or the replacement of a broad-spectrum antimicrobial with a narrower-spectrum antimicrobial. The aim of this review is to provide an overview of the available literature on the effectiveness and safety of ADE in critically ill patients, with a focus on special conditions such as anti-fungal therapy and high-risk categories. Although it is widely considered a safe strategy for antimicrobial stewardship (AMS), to date, there has been no assessment of the effect of de-escalation on the development of resistance. Conversely, some authors suggest that prolonged antibiotic treatment may be a side effect of de-escalation, especially in high-risk categories such as neutropenic critically ill patients and intra-abdominal infections (IAIs). Moreover, microbiological documentation is crucial for increasing ADE rates in critically ill patients with infections, and efforts should be focused on exploring new diagnostic tools to accelerate pathogen identification. For these reasons, ADE can be safely used in patients with infections, as confirmed by high-quality and reliable microbiological samplings, although further studies are warranted to clarify its applicability in selected populations.

We propose a neuromorphic framework to process the activity of human spinal motor neurons for movement intention recognition. This framework is integrated into 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 ${0}.{95} \pm {0}.{14}$ 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.

Abstract 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.

Not available.

Abstract 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

Abstract Background Whether respiratory physiology of COVID-19-induced respiratory failure is different from acute respiratory distress syndrome (ARDS) of other etiologies is unclear. We conducted a single-center study to describe respiratory mechanics and response to positive end-expiratory pressure (PEEP) in COVID-19 ARDS and to compare COVID-19 patients to matched-control subjects with ARDS from other causes. Methods Thirty consecutive COVID-19 patients admitted to an intensive care unit in Rome, Italy, and fulfilling moderate-to-severe ARDS criteria were enrolled within 24 h from endotracheal intubation. Gas exchange, respiratory mechanics, and ventilatory ratio were measured at PEEP of 15 and 5 cmH2O. A single-breath derecruitment maneuver was performed to assess recruitability. After 1:1 matching based on PaO2/FiO2, FiO2, PEEP, and tidal volume, COVID-19 patients were compared to subjects affected by ARDS of other etiologies who underwent the same procedures in a previous study. Results Thirty COVID-19 patients were successfully matched with 30 ARDS from other etiologies. At low PEEP, median [25th–75th percentiles] PaO2/FiO2 in the two groups was 119 mmHg [101–142] and 116 mmHg [87–154]. Average compliance (41 ml/cmH2O [32–52] vs. 36 ml/cmH2O [27–42], p = 0.045) and ventilatory ratio (2.1 [1.7–2.3] vs. 1.6 [1.4–2.1], p = 0.032) were slightly higher in COVID-19 patients. Inter-individual variability (ratio of standard deviation to mean) of compliance was 36% in COVID-19 patients and 31% in other ARDS. In COVID-19 patients, PaO2/FiO2 was linearly correlated with respiratory system compliance (r = 0.52 p = 0.003). High PEEP improved PaO2/FiO2 in both cohorts, but more remarkably in COVID-19 patients (p = 0.005). Recruitability was not different between cohorts (p = 0.39) and was highly inter-individually variable (72% in COVID-19 patients and 64% in ARDS from other causes). In COVID-19 patients, recruitability was independent from oxygenation and respiratory mechanics changes due to PEEP. Conclusions Early after establishment of mechanical ventilation, COVID-19 patients follow ARDS physiology, with compliance reduction related to the degree of hypoxemia, and inter-individually variable respiratory mechanics and recruitability. Physiological differences between ARDS from COVID-19 and other causes appear small.

IntroductionRemdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown.Materials and methodsProspective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality.ResultsWe included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, pConclusionsIn COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.

Sepsis is a leading cause of disability and mortality worldwide. The pathophysiology of sepsis relies on the maladaptive host response to pathogens that fosters unbalanced organ crosstalk and induces multi-organ dysfunction, whose severity was directly associated with mortality. In septic patients, etiologic interventions aiming to reduce the pathogen load via appropriate antimicrobial therapy and the effective control of the source infection were demonstrated to improve clinical outcomes. Nonetheless, extracorporeal organ support represents a complementary intervention that may play a role in mitigating life-threatening complications caused by sepsis-associated multi-organ dysfunction. In this setting, an increasing amount of research raised concerns about the risk of suboptimal antimicrobial exposure in critically ill patients with sepsis, which may be worsened by the concomitant delivery of extracorporeal organ support. Accordingly, several strategies have been implemented to overcome this issue. In this narrative review, we discussed the pharmacokinetic features of antimicrobials and mechanisms that may favor drug removal during renal replacement therapy, coupled plasma filtration and absorption, therapeutic plasma exchange, hemoperfusion, extracorporeal CO2 removal and extracorporeal membrane oxygenation. We also provided an overview of evidence-based strategies that may help the physician to safely prescribe effective antimicrobial doses in critically ill patients with sepsis-associated multi-organ dysfunction who receive extracorporeal organ support.

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.

(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.

Melanoma, one of the most lethal cutaneous cancers, is characterized by its ability to metastasize to other distant sites, such as the bone. Melanoma cells revealed a variable in vitro propensity to be attracted toward bone fragments, and melanoma-derived exosomes play a role in regulating the osteotropism of these cells. We have here investigated the lipid profiles of melanoma cell lines (LCP and SK-Mel28) characterized by different metastatic propensities to colonize the bone. We have purified exosomes from cell supernatants by ultracentrifugation, and their lipid composition has been compared to identify potential lipid biomarkers for different migration and invasiveness of melanoma cells. Matrix-assisted laser desorption ionization-time-of-flight/mass spectrometry (MALDI-TOF/MS) lipid analysis has been performed on very small amounts of intact parental cells and exosomes by skipping lipid extraction and separation steps. Statistical analysis has been applied to MALDI mass spectra in order to discover significant differences in lipid profiles. Our results clearly show more saturated and shorter fatty acid tails in poorly metastatic (LCP) cells compared with highly metastatic (SK-Mel28) cells, particularly for some species of phosphatidylinositol. Sphingomyelin, lysophosphatidylcholine, and phosphatidic acid were enriched in exosome membranes compared to parental cells. In addition, we have clearly detected a peculiar phospholipid bis(monoacylglycero)phosphate as a specific lipid marker of exosomes. MALDI-TOF/MS lipid profiles of exosomes derived from the poorly and highly metastatic cells were not significantly different.

Objectives To develop a population-based risk stratification model (COVID-19 Vulnerability Score) for predicting severe/fatal clinical manifestations of SARS-CoV-2 infection, using the multiple source information provided by the healthcare utilisation databases of the Italian National Health Service.Design Retrospective observational cohort study.Setting Population-based study using the healthcare utilisation database from five Italian regions.Participants Beneficiaries of the National Health Service, aged 18–79 years, who had the residentship in the five participating regions. Residents in a nursing home were not included. The model was built from the 7 655 502 residents of Lombardy region.Main outcome measure The score included gender, age and 29 conditions/diseases selected from a list of 61 conditions which independently predicted the primary outcome, that is, severe (intensive care unit admission) or fatal manifestation of COVID-19 experienced during the first epidemic wave (until June 2020). The score performance was validated by applying the model to several validation sets, that is, Lombardy population (second epidemic wave), and the other four Italian regions (entire 2020) for a total of about 15.4 million individuals and 7031 outcomes. Predictive performance was assessed by discrimination (areas under the receiver operating characteristic curve) and calibration (plot of observed vs predicted outcomes).Results We observed a clear positive trend towards increasing outcome incidence as the score increased. The areas under the receiver operating characteristic curve of the COVID-19 Vulnerability Score ranged from 0.85 to 0.88, which compared favourably with the areas of generic scores such as the Charlson Comorbidity Score (0.60). A remarkable performance of the score on the calibration of observed and predicted outcome probability was also observed.Conclusions A score based on data used for public health management accurately predicted the occurrence of severe/fatal manifestations of COVID-19. Use of this score may help health decision-makers to more accurately identify high-risk citizens who need early preventive or treatment interventions.

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.

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.

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.

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

• Bloodstream infections are quite frequent in COVID-19 patients undergoing vv-ECMO. • Primary and secondary bloodstream infections have peculiar microbiological profiles. • Appropriate treatment of bloodstream infections enables to minimize their impact on clinical outcomes. COVID-19 patients undergoing ECMO are at highly increased risk of nosocomial infections. To study incidence, clinical outcomes and microbiological features of bloodstream infections (BSI) occurring during ECMO in COVID-19 patients. Observational prospective cohort study enrolling consecutive COVID-19 patients undergoing veno-venous-ECMO in an Italian ICU from March 2020 to March 2022. In the study population of 68 patients (age 53 [49-60] years, 82% males), 30 (44%) developed bloodstream infections (BSI group) while 38 did not (N-BSI group) with an incidence of 32 events/1000 days of ECMO. In BSI group pre-ECMO respiratory support was shorter (6 [4–9] vs 9 [5–12] days, p = 0.02) and ECMO treatment was longer (18 [10–29] vs 11 [7–18] days, p = 0.03) than in N-BSI group. The overall ECMO and ICU mortality were 50% and 59%, respectively, without any inter-group difference (p = 1.00). A longer ECMO treatment was independently correlated with higher rate of BSI (p = 0.04, OR [95% CI] 1.06 [1.02–1.11]). Sixteen primary and 14 secondary infectious events were documented. Gram-positive pathogens were more common in primary than secondary BSI (88% vs 43%, p = 0.02) and Enterococcus faecalis (56%) was the most frequent one. Conversely, Gram-negative microorganisms were more often isolated in secondary rather than primary BSI (57% vs 13%, p = 0.02), with Acinetobacter baumannii (21%) and Pseudomonas aeruginosa (21%) as most represented species. The administration of Sars-CoV-2 antiviral drug showed independent correlation with a reduced rate of ICU mortality (p = 0.01, OR [95% CI] 0.22 [0.07–0.73]). Bloodstream infections represented a frequent complication without worsening clinical outcomes in our COVID-19 patients undergoing ECMO. Primary and secondary BSI events showed peculiar microbiological profiles. [ABSTRACT FROM AUTHOR]

The Mediterranean storm track constitutes a well-defined branch of the North Hemisphere storm track and is characterised by small but intense features and frequent cyclogenesis. The goal of this study is to assess the level of consensus among cyclone detection and tracking methods (CDTMs), to identify robust features and to explore sources of disagreement. A set of 14 CDTMs has been applied for computing the climatology of cyclones crossing the Mediterranean region using the ERA-Interim dataset for the period 1979–2008 as common testbed. Results show large differences in actual cyclone numbers identified by different methods, but a good level of consensus on the interpretation of results regarding location, annual cycle and trends of cyclone tracks. Cyclogenesis areas such as the north-western Mediterranean, North Africa, north shore of the Levantine basin, as well as the seasonality of their maxima are robust features on which methods show a substantial agreement. Differences among methods are greatly reduced if cyclone numbers are transformed to a dimensionless index, which, in spite of disagreement on mean values and interannual variances of cyclone numbers, reveals a consensus on variability, sign and significance of trends. Further, excluding ‘weak’ and ‘slow’ cyclones from the computation of cyclone statistics improves the agreement among CDTMs. Results show significant negative trends of cyclone frequency in spring and positive trends in summer, whose contrasting effects compensate each other at annual scale, so that there is no significant long-term trend in total cyclone numbers in the Mediterranean basin in the 1979–2008 period.