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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 Background Despite the growing body of evidence supporting the use of angiotensin II (ATII) in distributive shock, its integration into existing treatment algorithms requires careful consideration of factors related to patient comorbidities, hemodynamic parameters, cost-effectiveness, and risk–benefit balance. Moreover, several questions regarding its use in clinical practice warrant further investigations. To address these challenges, a group of Italian intensive care specialists (the panel) developed a consensus process using a modified Delphi technique. Methods The panel defined five clinical questions during an online scoping workshop and then provided a short list of statements related to each clinical question based on literature review and clinical experience. A total of 20 statements were collected. Two coordinators screened and selected the final list of statements to be included in the online survey, which consisted of 17 statements. The consensus was reached when ≥ 75% of respondents assigned a score within the 3-point range of 1–3 (disagreement) or 7–9 (agreement). Results Overall, a consensus on agreement was reached on 13 statements defining the existing gaps in scientific evidence, the possibility of evaluating the addition of drugs with different mechanisms of action for the treatment of refractory shock, the utility of ATII in reducing the catecholamine requirements in the treatment of vasopressor-resistant septic shock, and the effectiveness of ATII in treating patients in whom angiotensin-converting enzyme activity is reduced or pharmacologically blocked. It was widely shared that renin concentration can be used to identify patients who most likely benefit from ATII to restore vascular tone. Thus, the patients who might benefit most from using ATII were defined. Lastly, some potential barriers to the use of ATII were described. Conclusions ATII was recognized as a useful treatment to reduce catecholamine requirements in treating vasopressor-resistant septic shock. At the same time, the need for additional clinical trials to further elucidate the efficacy and safety of ATII, as well as investigations into potential mechanisms of action and optimization of treatment protocols in patients with refractory distributive shock, emerged.

Abstract Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients’ safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts’ opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.

Summary: Background: Endotype classification becomes the cornerstone of understanding sepsis pathogenesis. Macrophage activation-like syndrome (MALS) and immunoparalysis are the best recognized major endotypes, so far. Interferon-gamma (IFNγ) action on tissue macrophages stimulates the release of the cytotoxic chemokine CXCL9. It was investigated if this mechanism may be an independent sepsis endotype. Methods: In this cohort study, 14 patient cohorts from Greece, Germany and Italy were studied. The cohorts were 2:1 randomly split into discovery and validation sets. Sepsis was defined by the Sepsis-3 definitions and blood was sampled the first 24 h from meeting the Sepsis-3 definitions. Concentrations of IFNγ, CXCL9, IP-10 (IFNγ induced protein-10), soluble CD163 and ferritin were measured. The endotype of IFNγ-driven sepsis (IDS) was defined in the discovery set as the combination of a) blood IFNγ above a specified cut-off associated with the minimal risk for immunoparalysis (defined as ≥8000 HLA-DR receptors on CD45/CD14-monoytes); and b) increase of CXCL9. Results were compared to the validation set. Findings: 5503 patients were studied; 3670 in the discovery set and 1833 in the validation set. IDS was defined as IFNγ more than 3 pg/ml and CXCL9 more than 2200 pg/ml. The frequency of IDS in the discovery set was 19.9% (732 patients; 95% confidence intervals-CIs 18.7–21.3%) and in the validation set 20.0% (366 patients; 95% CIs 18.2–21.9%). Soluble CD163, a marker of macrophage activation, was greater in IDS and IDS had features distinct from MALS. The mortality in IDS patients was 43.0% (315 patients; 95% CIs 39.5–46.6%) in the discovery set and 40.4% in the validation set (148 patients; 95% CIs 35.5–45.5%) (p = 0.44 compared to patients of the discovery set). IDS was an independent risk factor for death in the presence of other endotypes, severity scores and organ dysfunctions of the multivariate model [hazard ratio 1.71 (95% CIs 1.45–2.01) in the discovery set and 1.70 (95% CIs 1.34–2.16) in the validation set]. Decreases of IFNγ and CXCL9 blood levels within the first 72 h were associated with better outcome. Interpretation: IDS is a new sepsis endotype independently associated with unfavorable outcome. Funding: Hellenic Institute for the Study of Sepsis; Horizon 2020 project ImmunoSep; Swedish Orphan BioVitrum AB (publ) and German Federal Ministry of Education and Research.

Abstract Background In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. Methods A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. Results The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. Conclusions Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

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.

Abstract Background Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. Materials and methods The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. Results Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13–9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23–11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07–33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76–10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01–4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42–1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. Conclusion PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Abstract Background The effects of awake prone position on the breathing pattern of hypoxemic patients need to be better understood. We conducted a crossover trial to assess the physiological effects of awake prone position in patients with acute hypoxemic respiratory failure. Methods Fifteen patients with acute hypoxemic respiratory failure and PaO2/FiO2 0.99) and ΔP L (9 [7–11] cmH2O vs. 8 [5–9], p = 0.17). Airway resistance and time constant were higher in prone vs. supine position (9 cmH2O s arbitrary units−3 [4–11] vs. 6 [4–9], p = 0.05; 0.53 s [0.32–61] vs. 0.40 [0.37–0.44], p = 0.03). Prone position increased EELI (3887 arbitrary units [3414–8547] vs. 1456 [959–2420], p = 0.002) and promoted V T distribution towards dorsal lung regions without affecting V T size and lung compliance: this generated lower dynamic strain (0.21 [0.16–0.24] vs. 0.38 [0.30–0.49], p = 0.004). The magnitude of pendelluft phenomenon was not different between study phases (55% [7–57] of V T in prone vs. 31% [14–55] in supine position, p > 0.99). Conclusions Prone position improves oxygenation, increases EELI and promotes V T distribution towards dependent lung regions without affecting V T size, ΔP L, lung compliance and pendelluft magnitude. Prone position reduces respiratory rate and increases ΔP ES because of positional increases in airway resistance and prolonged expiratory time. Because high ΔP ES is the main mechanistic determinant of self-inflicted lung injury, caution may be needed in using awake prone position in patients exhibiting intense ΔP ES. Clinical trail registeration: The study was registered on clinicaltrials.gov (NCT03095300) on March 29, 2017.

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.

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.

Abstract Introduction Helmet noninvasive support may provide advantages over other noninvasive oxygenation strategies in the management of acute hypoxemic respiratory failure. In this narrative review based on a systematic search of the literature, we summarize the rationale, mechanism of action and technicalities for helmet support in hypoxemic patients. Main results In hypoxemic patients, helmet can facilitate noninvasive application of continuous positive-airway pressure or pressure-support ventilation via a hood interface that seals at the neck and is secured by straps under the arms. Helmet use requires specific settings. Continuous positive-airway pressure is delivered through a high-flow generator or a Venturi system connected to the inspiratory port of the interface, and a positive end-expiratory pressure valve place at the expiratory port of the helmet; alternatively, pressure-support ventilation is delivered by connecting the helmet to a mechanical ventilator through a bi-tube circuit. The helmet interface allows continuous treatments with high positive end-expiratory pressure with good patient comfort. Preliminary data suggest that helmet noninvasive ventilation (NIV) may provide physiological benefits compared to other noninvasive oxygenation strategies (conventional oxygen, facemask NIV, high-flow nasal oxygen) in non-hypercapnic patients with moderate-to-severe hypoxemia (PaO2/FiO2 ≤ 200 mmHg), possibly because higher positive end-expiratory pressure (10–15 cmH2O) can be applied for prolonged periods with good tolerability. This improves oxygenation, limits ventilator inhomogeneities, and may attenuate the potential harm of lung and diaphragm injury caused by vigorous inspiratory effort. The potential superiority of helmet support for reducing the risk of intubation has been hypothesized in small, pilot randomized trials and in a network metanalysis. Conclusions Helmet noninvasive support represents a promising tool for the initial management of patients with severe hypoxemic respiratory failure. Currently, the lack of confidence with this and technique and the absence of conclusive data regarding its efficacy render helmet use limited to specific settings, with expert and trained personnel. As per other noninvasive oxygenation strategies, careful clinical and physiological monitoring during the treatment is essential to early identify treatment failure and avoid delays in intubation.

Leukaemia therapy may benefit from the use of antigens that are less restricted to individual donors. Here the authors engineered T cells with a TCR specific for a CD1c restricted lipid leukaemia antigen and show that they can protect against disease progression in mouse leukaemia xenograft models.

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 Implant-supported overdentures offer enhanced mechanical properties, which lead to better patient satisfaction and survival rates than conventional dentures. However, it is unclear whether these satisfaction levels and survival rates depend on the number of implants supporting the overdenture. Therefore, this systematic review aimed to compare maxillary overdentures supported by four or six splinted implants in terms of patient satisfaction, implant survival, overdenture survival, and prosthodontic complications. Methods Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), and EMBASE databases were systematically searched and complemented by hand searching from 2000 to 2019, employing a combination of specific keywords. Studies comparing the use of four versus six implants for supporting overdentures with at least one-year of follow-up after prosthesis installation and including ten fully edentulous patients were included. The risk of bias (RoB) was analyzed with Cochrane’s RoB 2 and Newcastle–Ottawa tools. Implants and prosthesis survival rates were analyzed by random-effects meta-analysis and expressed as risk ratios or risk differences, respectively, and by the non-parametric unpaired Fisher’s test. Results A total of 15 from 1865 articles were included, and reported follow-up times after implant placement ranged from 1 to 10 years. Irrespective of the number of implants used, high scores were reported by all studies investigating patient satisfaction. Meta-analysis and non-parametric Fisher’s test showed no statistical differences regarding the survival rate of implants (P = 0.34, P = 0.3) or overdentures (P = 0.74, P = 0.9) when using 4 versus 6 splinted implants to support overdentures, and no significant differences regarding prosthodontic complications were found between groups. Randomized studies presented high RoB and non-randomized studies presented acceptable quality. Conclusions Within the limits of this systematic review, we can conclude that the bar-supported overdenture on four implants is not inferior to the overdenture supported by six implants for rehabilitating the edentulous maxilla, in terms of patient satisfaction, survival rates of implants and overdentures, and prosthodontic complications.

Abstract Background Despite successful combined antiretroviral therapy (cART), the risk of non-AIDS defining cancers (NADCs) remains higher for HIV-infected individuals than the general population. The reason for this increase is highly disputed. Here, we hypothesized that T-cell receptor (TCR) γδ cells and/or mucosal-associated invariant T (MAIT) cells might be associated with the increased risk of NADCs. γδ T cells and MAIT cells both serve as a link between the adaptive and the innate immune system, and also to exert direct anti-viral and anti-tumor activity. Methods We performed a longitudinal phenotypic characterization of TCR γδ cells and MAIT cells in HIV-infected individuals developing Hodgkin’s lymphoma (HL), the most common type of NADCs. Cryopreserved PBMCs of HIV-infected individuals developing HL, matched HIV-infected controls without (w/o) HL and healthy controls were used for immunophenotyping by polychromatic flow cytometry, including markers for activation, exhaustion and chemokine receptors. Results We identified significant differences in the CD4+ T cell count between HIV-infected individuals developing HL and HIV-infected matched controls within 1 year before cancer diagnosis. We observed substantial differences in the cellular phenotype mainly between healthy controls and HIV infection irrespective of HL. A number of markers tended to be different in Vδ1 and MAIT cells in HIV+HL+ patients vs. HIV+ w/o HL patients; notably, we observed significant differences for the expression of CCR5, CCR6 and CD16 between these two groups of HIV+ patients. Conclusion TCR Vδ1 and MAIT cells in HIV-infected individuals developing HL show subtle phenotypical differences as compared to the ones in HIV-infected controls, which may go along with functional impairment and thereby may be less efficient in detecting and eliminating malignant cells. Further, our results support the potential of longitudinal CD4+ T cell count analysis for the identification of patients at higher risk to develop HL.

Background Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam. Methods We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least ≥24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality. Results The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy. Conclusions Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background (1,3)-β-d-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis. Methods This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-d-glucan was negative ((1,3)-β-d-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-d-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment. Results We randomized 108 patients into the (1,3)-β-d-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1–3] in the (1,3)-β-d-glucan group vs. 10 days [6–13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94–8.65], p

Abstract During critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. This so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill ICU population. It is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances. Bronchoscopic studies have revealed that the carina represents the densest site of bacterial DNA along healthy airways, with a tapering density with further bifurcations. This likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. Though bacterial DNA density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. The dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology. The body’s resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. Disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity. In this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia.

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.

Abstract Background In critically ill patients, the use of high tigecycline dosages (HD TGC) (200 mg/day) has been recently increasing but few pharmacokinetic/pharmacodynamic (PK/PD) data are available. We designed a prospective observational study to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of HD TGC in a cohort of critically ill patients with severe infections. Results This was a single centre, prospective, observational study that was conducted in the 20-bed mixed ICU of a 1500-bed teaching hospital in Rome, Italy. In all patients admitted to the ICU between 2015 and 2018, who received TGC (200 mg loading dose, then 100 mg q12) for the treatment of documented infections, serial blood samples were collected to measure steady-state TGC concentrations. Moreover, epithelial lining fluid (ELF) concentrations were determined in patients with nosocomial pneumonia. Amongst the 32 non-obese patients included, 11 had a treatment failure, whilst the other 21 subjects successfully eradicated the infection. There were no between-group differences in terms of demographic aspects and main comorbidities. In nosocomial pneumonia, for a target AUC0-24/MIC of 4.5, 75% of the patients would be successfully treated in presence of 0.5 mcg/mL MIC value and all the patients obtained the PK target with MIC ≤ 0.12 mcg/mL. In intra-abdominal infections (IAI), for a target AUC0-24/MIC of 6.96, at least 50% of the patients would be adequately treated against bacteria with MIC ≤ 0.5 mcg/mL. Finally, in skin and soft-tissue infections (SSTI), for a target AUC0-24/MIC of 17.9 only 25% of the patients obtained the PK target at MIC values of 0.5 mcg/mL and less than 10% were adequately treated against germs with MIC value ≥ 1 mcg/mL. HD TGC showed a relevant pulmonary penetration with a median and IQR ELF/plasma ratio (%) of 152.9 [73.5–386.8]. Conclusions The use of HD TGC is associated with satisfactory plasmatic and pulmonary concentrations for the treatment of severe infections due to fully susceptible bacteria (MIC

The aim of this work is to describe a case of severe disparallelism between two implants supporting a cement-retained bridge, placed in the maxilla, employing two custom-angled abutments. Fractured abutment screw and fractured abutment involved two implant restorations in the maxilla. Once prosthetic components have been removed, a new prosthetic rehabilitation has been planned. The divergence between the implants was measured, obtaining an angle of divergence of 39°. Then, two custom-angled titanium abutments and two metal-ceramic splinted crowns were realized.

Background & Aims: The characterization of T cells infiltrating hepatocellular carcinoma (HCC) provides information on cancer immunity and also on selection of patients with precise indication of immunotherapy. The aim of the study was to characterize T-cell populations within tumor tissue and compare them with non-neoplastic liver tissue as well as circulating cells of the same patients. Methods: The presence of unique cell populations was investigated in 36 HCC patients by multidimensional flow cytometry followed by t-distributed stochastic neighbor embedding analysis. Functional activity of tumor-infiltrating T cells was determined after activation by phorbol 12-myristate 13-acetate and ionomycin. Results: Within the tumor there were more cells expressing CD137 and ICOS than in non-neoplastic liver tissue, possibly after recent antigenic activation. These cells contained several populations, including the following: (1) functionally impaired, proliferating CD4+ cells co-expressing Inducible T-cell costimulator (ICOS) and T cell immunoreceptor with Ig and ITIM domains (TIGIT); (2) functionally active CD8+ cells co-expressing CD38 and Programmed cell-death protein 1 (PD1); and (3) CD4-CD8 double-negative T-cell receptor αβ and γδ cells (both non–major histocompatibility complex–restricted T cells). When the identified clusters were compared with histologic classification performed on the same samples, an accumulation of activated T cells was observed in immune-inflamed HCC. The same analyses performed in 7 patients receiving nivolumab treatment showed a remarkable reduction in the functionally impaired CD4+ cells, which returned to almost normal activity over time. Conclusions: Unique populations of activated T cells are present in HCC tissue, whose antigen specificity remains to be investigated. Some of these cell populations are functionally impaired and nivolumab treatment restores their responsiveness. The finding of ongoing immune response within the tumor shows which lymphocyte populations are impaired within the HCC and identifies the patients who might take benefit from immunotherapy. Keywords: Cancer Immunity, Immunotherapy, tSNE Analysis

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.

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease.

(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.

ABSTRACT Bacterial pneumonia is a challenging coronavirus disease 2019 (COVID-19) complication for intensive care unit (ICU) clinicians. Upon its implementation, the FilmArray pneumonia plus (FA-PP) panel’s practicability for both the diagnosis and antimicrobial therapy management of bacterial pneumonia was assessed in ICU patients with COVID-19. Respiratory samples were collected from patients who were mechanically ventilated at the time bacterial etiology and antimicrobial resistance were determined using both standard-of-care (culture and antimicrobial susceptibility testing [AST]) and FA-PP panel testing methods. Changes to targeted and/or appropriate antimicrobial therapy were reviewed. We tested 212 samples from 150 patients suspected of bacterial pneumonia. Etiologically, 120 samples were positive by both methods, two samples were culture positive but FA-PP negative (i.e., negative for on-panel organisms), and 90 were negative by both methods. FA-PP detected no culture-growing organisms (mostly Staphylococcus aureus or Pseudomonas aeruginosa) in 19 of 120 samples or antimicrobial resistance genes in two culture-negative samples for S. aureus organisms. Fifty-nine (27.8%) of 212 samples were from empirically treated patients. Antibiotics were discontinued in 5 (33.3%) of 15 patients with FA-PP-negative samples and were escalated/deescalated in 39 (88.6%) of 44 patients with FA-PP-positive samples. Overall, antibiotics were initiated in 87 (72.5%) of 120 pneumonia episodes and were not administered in 80 (87.0%) of 92 nonpneumonia episodes. Antimicrobial-resistant organisms caused 78 (60.0%) of 120 episodes. Excluding 19 colistin-resistant Acinetobacter baumannii episodes, AST confirmed appropriate antibiotic receipt in 101 (84.2%) of 120 episodes for one or more FA-PP-detected organisms. Compared to standard-of-care testing, the FA-PP panel may be of great value in the management of COVID-19 patients at risk of developing bacterial pneumonia in the ICU. IMPORTANCE Since bacterial pneumonia is relatively frequent, suspicion of it in COVID-19 patients may prompt ICU clinicians to overuse (broad-spectrum) antibiotics, particularly when empirical antibiotics do not cover the suspected pathogen. We showed that a PCR-based, culture-independent laboratory assay allows not only accurate diagnosis but also streamlining of antimicrobial therapy for bacterial pneumonia episodes. We report on the actual implementation of rapid diagnostics and its real-life impact on patient treatment, which is a gain over previously published studies on the topic. A better understanding of the role of that or similar PCR assays in routine ICU practice may lead us to appreciate the effectiveness of their implementation during the COVID-19 pandemic.

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.

Abstract Third molar removal surgery usually comes accompanied by postoperative discomfort, which could be influenced by the surgical approach chosen. This scoping systematic review aimed at compiling the available evidence focused on the influence of flap design, including envelope flap (EF), triangular flap (TF), and modified triangular flap (MTF), on postoperative pain, swelling, and trismus, as primary outcome measures, and any result mentioning healing promotion or delay, as secondary outcome measure, after mandibular third molar extraction surgery. An electronic search, complemented by a manual search, of articles published from 1999 to 2020 was conducted in the Medline (PubMed), EMBASE and Web of Science databases including human randomized controlled trials, prospective, and retrospective studies with at least 15 patients. The risk of bias of the included studies was assessed either with the Cochrane’s Risk of Bias tool or with the Newcastle-Ottawa scale. Every step of the review was performed independently and in duplicate. The initial electronic search recovered 2102 articles. After applying the inclusion criteria, 12 articles were included. For patient’s perceived postoperative pain, TF and MTF frequently reported better results than EF. For swelling, the literature is divided, despite a trend favoring EF. For trismus, data showed that its occurrence is mostly associated with the duration of the surgery rather than with the chosen flap. For healing, the limited data is inconclusive. Finally, randomized studies showed a high risk of bias, whereas nonrandomized studies were mostly of good quality and low risk of bias. Although there was no clear consensus regarding the influence of different flap designs for third mandibular molar extraction on postoperative clinical morbidities; the surgeon’s experience, estimated surgical difficulty, molar position and orientation, and surg ery duration should be considered when choosing among the different flap designs.

Abstract Background Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). Conclusions This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. Trial registration ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Abstract Background Data on high-flow nasal oxygen after thoracic surgery are limited and confined to the comparison with low-flow oxygen. Different from low-flow oxygen, Venturi masks provide higher gas flow at a predetermined fraction of inspired oxygen (FiO2). We conducted a randomized trial to determine whether preemptive high-flow nasal oxygen reduces the incidence of postoperative hypoxemia after lung resection, as compared to Venturi mask oxygen therapy. Methods In this single-center, randomized trial conducted in a teaching hospital in Italy, consecutive adult patients undergoing thoracotomic lung resection, who were not on long-term oxygen therapy, were randomly assigned to receive high-flow nasal or Venturi mask oxygen after extubation continuously for two postoperative days. The primary outcome was the incidence of postoperative hypoxemia (i.e., ratio of the partial pressure of arterial oxygen to FiO2 (PaO2/FiO2) lower than 300 mmHg) within four postoperative days. Results Between September 2015 and April 2018, 96 patients were enrolled; 95 patients were analyzed (47 in high-flow group and 48 in Venturi mask group). In both groups, 38 patients (81% in the high-flow group and 79% in the Venturi mask group) developed postoperative hypoxemia, with an unadjusted odds ratio (OR) for the high-flow group of 1.11 [95% confidence interval (CI) 0.41–3] (p = 0.84). No inter-group differences were found in the degree of dyspnea nor in the proportion of patients needing oxygen therapy after treatment discontinuation (OR 1.34 [95% CI 0.60–3]), experiencing pulmonary complications (OR 1.29 [95% CI 0.51–3.25]) or requiring ventilatory support (OR 0.67 [95% CI 0.11–4.18]). Post hoc analyses revealed that PaO2/FiO2 during the study was not different between groups (p = 0.92), but patients receiving high-flow nasal oxygen had lower arterial pressure of carbon dioxide, with a mean inter-group difference of 2 mmHg [95% CI 0.5–3.4] (p = 0.009), and were burdened by a lower risk of postoperative hypercapnia (adjusted OR 0.18 [95% CI 0.06–0.54], p = 0.002). Conclusions When compared to Venturi mask after thoracotomic lung resection, preemptive high-flow nasal oxygen did not reduce the incidence of postoperative hypoxemia nor improved other analyzed outcomes. Further adequately powered investigations in this setting are warranted to establish whether high-flow nasal oxygen may yield clinical benefit on carbon dioxide clearance. Trial registration ClinicalTrials.gov, NCT02544477. Registered 9 September 2015.

Background. To evaluate relationships between lung aeration assessed by lung ultrasound (LUS) with viscoelastic profiles obtained by thromboelastography (TEG) in COVID-19 respiratory failure. Methods. Retrospective analysis in a tertiary ICU in Rome, Italy. Forty invasively ventilated adults with COVID-19 underwent LUS and TEG assessment. A simplified LUS protocol consisting in scanning six areas, three per side, was adopted. A score from 0 to 3 was assigned to each area. TEG®6s was used to obtain viscoelastic hemostatic assay parameters which were compared to LUS score. Results. There was a significant inverse correlation between LUS score and static compliance of the respiratory system (Crs, rs −0.75; p < 0.001). We found a significant association between LUS and functional fibrinogen maximum amplitude (FF-MA): among 18 patients with LUS score ≤ 12, median FF-MA was 31 mm [IQR 28–39] whilst, among 22 patients with LUS score > 12, it was 46.3 mm [IQR 40–53], p = 0.0004. Median of the citrated recalcified kaolin-activated maximum amplitude (CK-MA) was 66.1 mm [64.4–68] in the LUS score ≤ 12 group, and 69.6 [68.5–70.7] when LUS score > 12, p < 0.002. Conclusions. The hypercoagulable profile as defined by elevated FF-MA and CK-MA may be associated with a low degree of lung aeration as assessed by LUS.

Summary: M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

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: Interleukin-6 signal blockade showed preliminary beneficial effects in treating inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Herein we describe the outcomes of off-label intravenous use of Sarilumab in severe SARS-CoV-2-related pneumonia. Methods: 53 patients with SARS-CoV-2 severe pneumonia received intravenous Sarilumab; pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards, live discharge rate in ICU treated patients and safety profile were recorded. Sarilumab 400 mg was administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and patients were followed for at least 14 days, unless previously discharged or dead. Findings: Of the 53 SARS-CoV-2pos patients receiving Sarilumab, 39(73·6%) were treated in medical wards [66·7% with a single infusion; median PaO2/FiO2:146(IQR:120–212)] while 14(26·4%) in ICU [92·6% with a second infusion; median PaO2/FiO2: 112(IQR:100–141.5)].Within the medical wards, 7(17·9%) required ICU admission, 4 of whom were re-admitted to the ward within 5–8 days. At 19 days median follow-up, 89·7% of medical inpatients significantly improved (46·1% after 24 h, 61·5% after 3 days), 70·6% were discharged from the hospital and 85·7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64·2% were discharged from ICU to the ward and 35·8% were still alive at the last follow-up. Overall mortality rate was 5·7%. Interpretation: IL-6R inhibition appears to be a potential treatment strategy for severe SARS-CoV-2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical outcome and good safety.

Introduction Nosocomial pneumonia develops after ≥48 h of hospitalisation and is classified as ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP); the latter may require mechanical ventilation (V-HAP) or not (NV-HAP). Main findings VAP and HAP affect a significant proportion of hospitalised patients and are characterised by poor clinical outcomes. Among them, V-HAP has the greatest 28-day mortality rate followed by VAP and NV-HAP (27.8% versus 18% versus 14.5%, respectively). However, no differences in terms of pathophysiology, underlying microbiological pathways and subsequent therapy have been identified. International guidelines suggest specific flow charts to help clinicians in the therapeutic management of such diseases; however, there are no specific recommendations beyond VAP and HAP classification. HAP subtypes are scarcely considered as different entities and the lack of data from the clinical scenario limits any final conclusion. Hopefully, recent understanding of the pathophysiology of such diseases, as well as the discovery of new therapies, will improve the outcome associated with such pulmonary infections. Conclusion Nosocomial pneumonia is a multifaced disease with features of pivotal interest in critical care medicine. Due to the worrisome data on mortality of patients with nosocomial pneumonia, further prospective studies focused on this topic are urgently needed.

Non-polymorphic MHC class I-related molecule MR1 presents antigenic bacterial metabolites to mucosal-associated invariant T (MAIT) cells and self-antigens to MR1-restricted T (MR1T) cells. Both MR1-restricted T cell populations are readily identified in healthy individuals, with MAIT cells accounting for 1–10% of circulating T cells, while MR1T cells have frequencies comparable to peptide-specific T cells (

The Fungitell assay (FA) and the Wako β-glucan test (GT) are employed to measure the serum/plasma 1,3-β-D-glucan (BDG), a well-known invasive fungal disease biomarker. Data to convincingly and/or sufficiently support the GT as a valuable alternative to the FA are yet limited. In this study, we evaluated the FA and the GT to diagnose invasive aspergillosis (IA), invasive candidiasis (IC), and Pneumocystis jirovecii pneumonia (PJP). The FA and GT performances were compared in sera of patients with IA (n = 40), IC (n = 78), and PJP (n = 17) with respect to sera of control patients (n = 187). Using the manufacturer's cutoff values of 80 pg/mL and 11 pg/mL, the sensitivity and specificity for IA diagnosis were 92.5% and 99.5% for the FA and 60.0% and 99.5% for the GT, respectively; for IC diagnosis were 100.0% and 97.3% for the FA and 91.0% and 99.5% for the GT, respectively; for PJP diagnosis were 100.0% and 97.3% for the FA and 88.2% and 99.5% for the GT, respectively. When an optimized cutoff value of 7.0 pg/mL for the GT was used, the sensitivity and specificity were 80.0% and 97.3% for IA diagnosis, 98.7% and 97.3% for IC diagnosis, and 94.1% and 97.3% for PJP diagnosis, respectively. At the 7.0-pg/mL GT cutoff, the agreement between the assays remained and/or became excellent for IA (95.1%), IC (97.3%), and PJP (96.5%), respectively. In conclusion, we show that the GT performed as well as the FA only with a lowered cutoff value for positivity. Further studies are expected to establish the equivalence of the two BDG assays.

In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions.

Background: Thrombosis with cardiovascular involvement is a crucial complication in COVID-19 infection. COVID-19 infects the host by the angiotensin converting enzyme-2 receptor (ACE2r), which is expressed in endothelial cells too. Thus, COVID-related thrombotic events might be due to endothelial dysfunction. IL-6 is one of the main cytokines involved in the COVID-19 inflammatory storm. Some evidence indicates that Vitamin D (VitD) has a protective role in COVID-19 patients, but the molecular mechanisms involved are still debated. Thus, we investigated the effect of VitD on Tissue Factor and adhesion molecules (CAMs) in IL-6-stimulated endothelial cells (HUVEC). Moreover, we evaluated levels of the ACE2r gene and proteins. Finally, we studied the modulation of NF-kB and STAT3 pathways. Methods: HUVEC cultivated in VitD-enriched medium were stimulated with IL-6 (0.5 ng/mL). The TF gene (RT-PCR), protein (Western blot), surface expression (FACS) and procoagulant activity (FXa generation assay) were measured. Similarly, CAMs soluble values (ELISA) and ACE2r (RT-PCR and Western blot) levels were assessed. NF-kB and STAT3 modulation (Western blot) were also investigated. Results: VitD significantly reduced TF expression at both gene and protein levels as well as TF-procoagulant activity in IL-6-treated HUVEC. Similar effects were observed for CAMs and ACE2r expression. IL-6 modulates these effects by regulating NF-κB and STAT3 pathways. Conclusions: IL-6 induces endothelial dysfunction with TF and CAMs expression via upregulation of ACE2r. VitD prevented these IL-6 deleterious effects. Thus, it might be speculated that this is one of the hypothetical mechanism(s) by which VitD exerts its beneficial effects in COVID-19 infection.