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Introduction: Patients with hematologic malignancies are more likely to develop severe and prolonged SARS-CoV-2 infection, often showing viral persistence despite the use of authorized antivirals. Herein, we report the cases of four patients who received rituximab for different conditions and developed persistent COVID-19 treated with an extended course of dual antivirals, Nirmatrelvir/Ritonavir and Remdesivir. Moreover, we describe the pharmacokinetics and pharmacogenetics (PK/PG) characteristics of Nirmatrelvir/Ritonavir and Remdesivir treatment in two of these patients. Methods: Plasma specimens for evaluation of trough concentrations (Ctrough) were collected 10 min before the daily dose administration, in addition to 3 h (Cmax), 4 h (C4h), 6 h (C6h) and 1 h (Cmax) after the administration of Nirmatrelvir/Ritonavir and Remdesivir, respectively. The following gene single-nucleotide polymorphisms (SNPs) were investigated: ABCB1 3435 (rs1045642) C > T, ABCB1 1236 (rs1128503) C > T, PXR 63396 (rs2472667) T > C, CYP2D6 (rs1135840) G > C, and CYP3A4*1B (rs2740574) G > A. Results: Double antiviral treatment was successful in terms of symptoms resolution, whereas three out of four patients achieved microbiological eradication. Based on our results, concentrations of Nirmatrelvir ranging from 50 to 5000 ng/mL were effective, whereas a higher concentration (range 1068–3377 ng/mL), compared to that previously reported in patients with similar weight and BMI, was evidenced for Ritonavir. Considering the genetic variant analysis, ABCB1 3435 CT and 1236 CT genotypes were found in patient 1; and ABCB1 3435 CC and 1236 CC in patient 2. In conclusion, this real-life study supports the usefulness of TDM and genetics in immunocompromised patients with persistent SARS-CoV-2 infection, a challenging setting for clinicians in which personalized medicine may improve outcome.

Herpes zoster ophthalmicus results from the reactivation of the latent varicella zoster virus, affecting the first branch of the trigeminal nerve. In 20–70% of cases, Zoster Ophthalmicus can lead to ocular involvement, affecting various orbital structures. Orbital myositis is a rare but severe complication of herpes zoster ophthalmicus. We present a case of a 52-year-old man with no significant medical history who developed zoster-associated right ocular myositis and dacryocystitis. He was treated with intravenous acyclovir and oral steroids. A review of the literature identified 29 patients across 19 studies. The median age was 61 years, with a slight female predominance. In 55% of cases, the patients had no notable medical history. The most common presentation of myositis involved all oculomotor muscles. There were 22 cases who were treated with intravenous antiviral therapy and 19 received steroids. A full resolution of symptoms was achieved in 51.7% of patients. Zoster-related orbital myositis is a rare complication that should be considered even in immunocompetent individuals. It may occur either before or after the appearance of a vesicular rash. Magnetic resonance imaging is the preferred radiological exam for assessing orbital involvement. Intravenous antiviral therapy should be started within 72 h of symptom onset, and its combination with systemic corticosteroids appears to be an effective treatment for zoster-related ocular myositis.

Recent developments in modeling and analysis of nanostructures are illustrated and discussed in this paper. Starting with the early theories of nonlocal elastic continua, a thorough investigation of continuum nano-mechanics is provided. Two-phase local/nonlocal models are shown as possible theories to recover consistency of the strain-driven purely integral theory, provided that the mixture parameter is not vanishing. Ground-breaking nonlocal methodologies based on the well-posed stress-driven formulation are shown and commented upon as effective strategies to capture scale-dependent mechanical behaviors. Static and dynamic problems of nanostructures are investigated, ranging from higher-order and curved nanobeams to nanoplates. Geometrically nonlinear problems of small-scale inflected structures undergoing large configuration changes are addressed in the framework of integral elasticity. Nonlocal methodologies for modeling and analysis of structural assemblages as well as of nanobeams laying on nanofoundations are illustrated along with benchmark applicative examples.

Submarine caves are important biodiversity reservoirs, but there is little information about the biota of marine caves in the Southwestern Atlantic. Here, we describe three submarine cavities and their sponge communities on the Fernando de Noronha Archipelago, Northeast Brazil. The underwater cavities were explored and collections were made through scuba diving from 5 to 18 m depths. Sapata Cave has a wide semi-dark zone near the entrance, a narrow transition zone, and a dark chimney, which is closed at the top. Ilha do Meio Cave is narrower and shallower than Sapata Cave, but has a long passage that leads to two completely dark rooms. Pedras Secas Tunnel has only a semi-dark zone with high water movement. The sponge communities in the semi-dark zones of the three cavities are rich and dominated by the classes Demospongiae and Homoscleromorpha, but Calcarea are also common. The transition zones of both caves are dominated by a desma-bearing sponge, thinly encrusting spirastrellids, and small Homoscleromopha and Calcarea. The dark zone in Ilha do Meio Cave is almost azoic, with only three species. This study has increased the number of sponge species known in submarine cavities on Fernando de Noronha from 29 to 69, highlighting the great richness of the sponge communities in these cryptic environments.

Ceftobiprole is a fifth-generation cephalosporin approved by European and American regulatory agencies for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Ceftobiprole administration is useful in severe CAP as well as HAP where the potential is to save other β-lactams including carbapenems or linezolid/vancomycin in clinical practice. The aim of this study was to report the real-world evidence of ceftobiprole in patients with CAP and HAP in a single center. In this retrospective study, we included 159 patients with CAP or HAP: 105 (66%) had CAP and 54 (34%) had HAP. The median age was 70 years (IQR 60–77), the median Charlson Comorbidity Index was 5 (IQR 3–7.5) and baseline INCREMENT ESBL score was 8 (IQR 6–11). Ceftobiprole was mostly given as a combination treatment (77%) or as a carbapenem-sparing strategy (44%). There were no differences in mortality between shorter and longer duration of treatment (p = 0.93) or between first-line (HR 1.00, C.I. 0.46–2.17, p = 0.989) and second-line therapy. Ceftobiprole use in CAP or HAP in the real world is effective as a first- and second-line treatment as well as a carbapenem-sparing strategy. Further studies are needed to explore the full potential of ceftobiprole, including its real-world use in antimicrobial stewardship programs.

Background and Objectives: the principal purpose of this literature review is to cluster adults with hematological malignancies after treatment or on maintenance with obinutuzumab who experienced disseminated EV infection to understand clinical characteristics and outcome of this rare condition in these patients. We report the first clinical case of a male affected by follicular lymphoma treated with immune-chemotherapy including obinutuzumab who was affected by disseminated EV infection with cardiovascular involvement. Materials and Methods: this narrative review summarizes all the research about disseminated EV infection in immunosuppressed adult patients treated with obinutuzumab from January 2000 to January 2024 using the Scale for the Assessment of Narrative Review Articles (SANRA) flow-chart. We performed a descriptive statistic using the standard statistical measures for quantitative data. Results: we included six studies, five case reports, and one case report with literature analysis. We collected a total of seven patients, all female, with disseminated EV infection. The most common signs and clinical presentations of EV infection were fever and encephalitis symptoms (N = 6, 85.7%), followed by hepatitis/acute liver failure (N = 5, 71.4%). Conclusions: onco-hematological patients who receive immune-chemotherapy with a combination of treatments which depress adaptative immunity, which includes the antiCD20 obinutuzumab, could be at higher risk of disseminated EV infection, including CNS and cardiac involvement.

Left ventricular assist devices (LVADs) have been increasingly used as a valid option to improve the prognosis and reduce the symptoms of end-stage heart failure. However, long-term complications, mostly infections and coagulation disorders, are frequent. We described the epidemiology and risk factors for nosocomial infections (NIs) in a cohort of adult patients who underwent continuous-flow LVAD implant between January 2010 and December 2017 in Turin, Italy. Secondary outcomes were the prevalence of multidrug-resistant (MDR) bacteria and mortality. Results: Overall, 64 LVADs were implanted. A total of 32 (50%) patients experienced at least one episode of NI, with a total of 46 infectious events. VAD-related infections occurred in 22 patients (68.8%). Non VAD-related NIs occurred in 12 patients (37.5%), mainly low respiratory tract infections. Length of intensive care unit admission was a risk factor for NI (OR 1.224, 95%CI; 1.049, 1.429). Gram-negative bacilli were responsible for 58.8% of VAD-related infections and 79.5% of non-VAD related infections. In sixteen patients (50%), at least one episode of infection was related to an MDR strain. INTERMACS class and length of MV were independent risk factors for NIs by MDR strains (respectively, OR 2.12, 95%CI: 1.08, 6.80; p = 0.02 and OR 1.46, 95%CI: 1.07, 5.52, p = 0.047). In-hospital mortality was 6.3%. No differences in mortality were observed between infected and non-infected patients (p = 0.61) even when caused by MDR strains (p = 0.143). Conclusion: the rate of nosocomial infections in LVAD patients is associated with the length of ICU admission, and the etiology of nosocomial infection after LVAD implant is mainly due to GNB, including a high rate of MDR strains, especially KPC-KP and MDR PA.

Background and Objectives: Stenotrophomonas maltophilia is a ubiquitous, aerobic, Gram-negative bacillus causing increasing concern in patients affected by haematological malignancies. Materials and Methods: We report a case series from two centres in Northern Italy to describe the characteristics, outcome and microbiological response of S. maltophilia infections in patients with haematological malignancies and/or allogenic hematopoietic stem cell transplantation (aHSCT). Results: Ten patients were included. The median age was 67 years, and seven patients (70%) were males. The median Charlson Comorbidity Index was 6 (IQR: 4–8). The most frequent haematological comorbidities were acute myeloid leukaemia (AML; n = 3; 30%) and non-Hodgkin’s lymphoma (n = 3; 30%). Three (30%) patients underwent aHSCT before infection, all for AML. All the patients had undergone a recent antibiotics course and had an indwelling central venous catheter before infection. The main clinical presentations were nosocomial pneumonia, with (2; 20%) or without (4; 40%) secondary bloodstream infection and CRBSI (3; 30%). Four patients were treated with cefiderocol in monotherapy or combinations therapy with cotrimoxazole. The rest of the patients were treated with cotrimoxazole or levofloxacin in monotherapy. Conclusions: Despite a high rate of clinical improvement (90%) after starting antimicrobial therapy, we faced high 30-day mortality (30%) and in-hospital mortality (50%) rates in a highly comorbid population.

(1) Background: The widespread use of MALDI-TOF coupled to mass spectrometry has improved diagnostic accuracy by identifying uncommon bacteria. Among Enterobacterales, Pantoea species have been seen to be implicated in several human infections, but their clinical and microbiological framework is currently based on a few anecdotal reports. (2) Methods: We conducted this five-year (2018–2023) single-center study aimed at investigating the prevalence and clinical and microbiological findings of Pantoea species bloodstream infections. (3) Results: Among the 4996 bloodstream infection Gram-negative isolates collected during the study period, Pantoea species accounted for 0.4% (n = 19) of isolates from 19 different patients, 5 of them being pediatric cases. Among Pantoea species isolates, P. agglomerans was the most frequently detected (45%; n = 9) followed by P. eucrina (30%; n = 6) and P. septica (15%; n = 3). Malignancy (35.7%) in adults and malignancy (40%) and cerebrovascular disease following meconium aspiration (40%) in pediatric patients as comorbidities and shivering and/or fever following parenteral infusion (36.8%) as a symptom/sign of Pantoea species bloodstream infection onset were the most frequently observed clinical features. Among adults, primary bloodstream infection was the most frequent (50%), whereas among pediatric patients, the most commonly identified sources of infection were catheter-related (40%) and the respiratory tract (40%). Overall, Pantoea species bloodstream infection isolates displayed high susceptibility to all the antibiotics except for ampicillin (63.2%), fosfomycin (73.7%), and piperacillin/tazobactam (84.2%). Targeted antibiotic treatment was prescribed as monotherapy for adults (71.4%) and combination therapy for pediatric patients (60%). The most prescribed antibiotic regimens were piperacillin/tazobactam (21.4%) in adults and meropenem- (40%) and aminoglycoside-containing (40%) antibiotics in pediatric patients. The overall 28-day all-cause mortality rate was 5.3% (n = 1). (4) Conclusions: The prevalence and 28-day mortality rate of Pantoea species bloodstream infections were low. The prescription of targeted therapy including broad-spectrum antibiotics could indicate an underestimation of the specific involvement of the Pantoea species in the onset of the disease, warranting further studies defining their pathogenic potential.

Prolonged SARS-CoV-2 infections are widely described in immunosuppressed patients, but safe and effective treatment strategies are lacking. We aimed to outline our approach to treating persistent COVID-19 in patients with immunosuppression from different causes. In this case series, we retrospectively enrolled all immunosuppressed patients with persistent SARS-CoV-2 infections treated at our centers between March 2022 and February 2023. Patients received different sequential or combination regimens, including antivirals (remdesivir, nirmatrelvir/ritonavir, or molnupiravir) and/or monoclonal antibodies (mAbs) (tixagevimab/cilgavimab or sotrovimab). The main outcome was a complete virological response (negative SARS-CoV-2 RT-PCR on nasopharyngeal swabs) at the end of treatment. Fifteen patients were included as follows: eleven (11/15; 73%) with hematological disease and four (4/15; 27%) with recently diagnosed HIV/AIDS infection. Six patients (6/15; 40%) received a single antiviral course, four patients (4/15; 27%) received an antiviral and mAbs sequentially, and two patients (13%) received three lines of treatment (a sequence of three antivirals or two antivirals and mAbs). A combination of two antivirals or one antiviral plus mAbs was administered in three cases (3/15, 20%). One patient died while still positive for SARS-CoV-2, while fourteen (14/15; 93%) tested negative within 16 days after the end of treatment. The median time to negativization since the last treatment was 2.5 days. Both sequential and combination regimens used in this study demonstrated high efficacy and safety in the high-risk group of immunosuppressed patients.

Background: The relationship between superinfection by multidrug-resistant Gram-negative bacteria and mortality among SARS-CoV-2 hospitalized patients is still unclear. Carbapenem-resistant Acinetobacter baumannii and carbapenemase-producing Enterobacterales are among the most frequently isolated species when it comes to hospital-acquired superinfections among SARS-CoV-2 patients. Methods: Herein, a retrospective study was carried out using data from adult patients hospitalized for COVID-19. The interaction between in-hospital mortality and rectal carriage and superinfection by carbapenemase-producing Enterobacterales and/or carbapenem-resistant Acinetobacter baumannii was assessed. Results: The incidence of KPC-producing Klebsiella pneumoniae and/or carbapenem-resistant Acinetobacter baumannii rectal carriage was 30%. Bloodstream infection and/or pneumonia due to KPC-producing Klebsiella pneumoniae and/or carbapenem-resistant Acinetobacter baumannii occurred in 20% of patients. A higher Charlson comorbidity index (OR 1.41, 95% CI 1.24–1.59), being submitted to invasive mechanical ventilation/ECMO ≥ 96 h (OR 6.34, 95% CI 3.18–12.62), being treated with systemic corticosteroids (OR 4.67, 95% CI 2.43–9.05) and having lymphopenia at the time of admission (OR 0.54, 95% CI 0.40–0.72) were the features most strongly associated with in-hospital mortality. Conclusions: Although KPC-producing Klebsiella pneumoniae and/or carbapenem-resistant Acinetobacter baumannii rectal carriage, and/or bloodstream infection/pneumonia were diagnosed in a remarkable percentage of COVID-19 patients, their impact on in-hospital mortality was not significant. Further studies are needed to assess the burden of antimicrobial resistance as a legacy of COVID-19 in order to identify future prevention opportunities.

mRNA-based vaccines were effective in contrasting SARS-CoV-2 infection. However, they presented several limitations of storage and supply chain, and their parenteral administration elicited a limited mucosal IgA immune response. Extracellular vesicles (EVs) have been recognized as a mechanism of cell-to-cell communication well-preserved in all life kingdoms, including plants. Their membrane confers protection from enzyme degradation to encapsulated nucleic acids favoring their transfer between cells. In the present study, EVs derived from the juice of an edible plant (Citrus sinensis) (oEVs) were investigated as carriers of an orally administered mRNA vaccine coding for the S1 protein subunit of SARS-CoV-2 with gastro-resistant oral capsule formulation. The mRNA loaded into oEVs was protected and was stable at room temperature for one year after lyophilization and encapsulation. Rats immunized via gavage administration developed a humoral immune response with the production of specific IgM, IgG, and IgA, which represent the first mucosal barrier in the adaptive immune response. The vaccination also triggered the generation of blocking antibodies and specific lymphocyte activation. In conclusion, the formulation of lyophilized mRNA-containing oEVs represents an efficient delivery strategy for oral vaccines due to their stability at room temperature, optimal mucosal absorption, and the ability to trigger an immune response.

This work presents the results of long-term deep-water observations carried out in the southwestern Adriatic margin. Hydrodynamics and thermohaline measurements were carried out in the last 100 m of the water column using two long-term moorings placed at two different locations along the western sector of the Adriatic continental margin (open slope vs. submarine canyon). The observations, carried out over a period of almost 10 years, made it possible to define the intra- and interannual deep-water dynamics, which are mainly influenced by the passage of cold, dense water. The hydrodynamic field is influenced by seasonal behavior and varies from year to year, with no clear temporal trend or periodicity. Thermohaline properties follow hydrodynamics but also show a climatological trend toward higher temperatures and salinity. The combination and variability of preconditioning factors explains the interannual variability in dense water passage at the mooring sites triggering the formation of dense water in the northern Adriatic. The impulsive nature of the dense water flow, which is difficult to capture with sporadic oceanographic surveys, and its linkage with the large-scale atmospheric circulation make continuous monitoring essential to answer open questions about cascading processes and deep-water dynamics under a global change scenario.

Strongyloides and cytomegalovirus co-infections are rarely reported, even though they are distinguished by high morbidity and mortality, especially in immunocompromised hosts. We narratively reviewed the literature on reported cases of Strongyloides and CMV co-infections in immunosuppressed patients. Most cases occurred in males with a median age of 47 (IQR, 37–59). Strongyloides/CMV co-infections occurred among immunocompromised hosts, especially in solid organ transplants and hematological or rheumatological diseases. Most of the patients underwent a course of steroid treatment before the diagnosis of co-infections. Other common immunomodulatory agents were tacrolimus and mycophenolate. The first clinical manifestations of co-infections were mainly gastrointestinal, followed by respiratory symptoms. CMV was, in most patients, co-infected with an isolated reactivation, although Strongyloides manifested especially as hyperinfection syndrome. Ganciclovir and ivermectin are the mainstays of CMV and Strongyloides treatment. However, the treatment mortality reported in this narrative review is around 52.4%. Interestingly secondary bacterial infections are common in CMV/Strongyloides-infected patients.

Staphylococci are one of the most common causes of biofilm-related infections. Such infections are hard to treat with conventional antimicrobials, which often lead to bacterial resistance, thus being associated with higher mortality rates while imposing a heavy economic burden on the healthcare system. Investigating antibiofilm strategies is an area of interest in the fight against biofilm-associated infections. Previously, a cell-free supernatant from marine-sponge-associated Enterobacter sp. inhibited staphylococcal biofilm formation and dissociated the mature biofilm. This study aimed to identify the chemical components responsible for the antibiofilm activity of Enterobacter sp. Scanning electron microscopy confirmed that the aqueous extract at the concentration of 32 μg/mL could dissociate the mature biofilm. Liquid chromatography coupled with high-resolution mass spectrometry revealed seven potential compounds in the aqueous extract, including alkaloids, macrolides, steroids, and triterpenes. This study also suggests a possible mode of action on staphylococcal biofilms and supports the potential of sponge-derived Enterobacter as a source of antibiofilm compounds.

To our knowledge, we have described the first case of Strongyloides/Cytomegalovirus (CMV) concomitant infection that occurred in a European country. The patient was a 76-year-old woman affected by relapsed non-Hodgkin lymphoma who presented interstitial pneumonia with a rapidly progressive worsening of respiratory insufficiency, leading to cardiac dysfunction and consequent death. CMV reactivation is a common complication in immunocompromised patients, while hyperinfection/disseminated strongyloidiasis (HS/DS) is rare in low endemic regions, but has been widely described in Southeast Asia and American countries. HS and DS are two consequences of the failure of infection control by the immune system: HS is the uncontrolled replication of the parasite within the host and DS the spreading of the L3 larvae in organs other than the usual replication sites. Only a few cases of HS/CMV infection have been reported in the literature, and only in one patient with lymphoma as an underlying disease. The clinical manifestations of these two infections overlap, usually leading to a delayed diagnosis and a consequent poor outcome.

Background: COVID-19 is characterized by an uncontrolled inflammatory response with high pro-inflammatory cytokine production through the activation of intracellular pathways, such as mitogen-activated protein kinase (MAPK). Viruses are able to exploit the MAPK pathway to their advantage; this pathway relevance to severe COVID-19 is poorly described. The aim of this study was to quantify biomarkers involved in the MAPK pathway and to clarify its possible role in affecting some COVID-19-related clinical features. Methods: H-RAS, C-RAF, MAPK1, MAPK2, and ERK were quantified through ELISA, and genetic polymorphisms were evaluated through real-time PCR. Results: We prospectively recruited 201 individuals (158 positive and 43 negative for SARS-CoV-2): 35 were male, and their median age was 65 years. MAPK-related biomarker levels were increased in SARS-CoV-2-positive participants (n = 89) compared to negative ones (n = 29). Dyspnea was reported by 48%; this symptom was associated with PBMC C-RAF levels in positive participants (p = 0.022) and type of ventilation (p = 0.031). The highest degree of ventilation was used by 8% for invasive ventilation and 41% for continuous positive airway pressure (CPAP). Conclusions: This is the first study that showed a possible contribution of MAPK-related biomarkers in affecting COVID-19 clinical features, and this may be relevant for identifying COVID-19 positive participants at risk of serious complications.

Bloodstream infections (BSI) are an increasing cause of admissions to hospitals. Non-hospital-acquired BSI are defined by blood cultures that are positive less than 48 hours after admission, but a relevant difference exists between community-acquired and healthcare-associated (HCA) BSI in terms of risk of multidrug resistance (MDR). We planned a retrospective study in three different cohorts in order to develop and to temporally and spatially validate an easy and rapid prognostic model for identifying MDR non-hospital-acquired (non-HA) BSI. The pathogens most involved in BSI are Staphylococcus spp. and Escherichia coli, responsible for about 75% of all MDR isolated. The model includes age, gender, long-term care facility admission, immunocompromise, any recent invasive procedures and central line placement, recent intravenous treatment and antibiotic treatment. It shows an acceptable performance, especially for intermediate probabilities of MDR infection, with a C-index of 70%. The model was proposed in a nomogram that could allow better targeting of antibiotic therapy for non-HA BSI admitted in hospital. However, it should be further validated to determine its applicability in other populations.

Oritavancin is a long-acting lipoglycopeptide with in vitro activity against Gram-positive pathogens, as well as good bactericidal activity and sterilisation ability in biofilm. It has been approved for acute bacterial skin and skin structure infections (ABSSSI), but recent reports have demonstrated possible off-label uses, such as for vancomycin resistant enterococci (VRE), deep-seated infections including those involving prosthetic material and invasive infections. The aim of this work is to review the uses of oritavancin outside of ABSSSI, focusing on its real-life applications on infective endocarditis, catheter- or device-related infections, bloodstream infections, and bone and prosthetic joint infections in humans, as well as possible future applications. We performed a narrative review, collecting the literature published between 1 December 2002 and 1 November 2022 on PubMed and the Cochrane Library using the term ‘oritavancin’. Available studies have shown how effective it is in different settings, suggesting an opportunity for step-down strategies or outpatient management of infections requiring a long duration of antibiotic treatment. So far, evidence is still scarce, and limited to a few studies and case reports, mostly focusing on Staphylococcus aureus as the major isolate. Concerns about fluid intake for dilution and interaction with coagulation markers also need to be taken into account. Further studies are required in order to assess the safety and effectiveness of Oritavancin in vascular, prosthetic, or device-related infections, as well as in resistant Gram-positive bacteria or enterococcal infections.

The use of venoarterial (VA) extracorporeal membrane oxygenation therapy (ECMO) in patients admitted to cardiac intensive care units (CICU) has increased. Data regarding infections in this population are scarce. In this retrospective study, we analyzed the risk factors, outcome, and predictors of in-hospital mortality due to nosocomial infections in patients with ECMO admitted to a single coronary intensive care unit between July 2013 and March 2019 treated with VA-ECMO for >48 h. From 69 patients treated with VA-ECMO >48 h, (median age 58 years), 29 (42.0%) patients developed 34 episodes of infections with an infection rate of 0.92/1000 ECMO days. The most frequent were ventilator-associated pneumonia (57.6%), tracheobronchitis (9.1%), bloodstream infections (9.1%), skin and soft tissue infections (9.1%), and cytomegalovirus reactivation (9.1%). In-hospital mortality was 47.8%, but no association with nosocomial infections was found (p = 0.75). The number of days on ECMO (OR 1.14, 95% CI 1.01–1.30, p = 0.029) and noninfectious complications were higher in the infected patients (OR: 3.8 95% CI = 1.05–14.1). A higher baseline creatinine value (OR: 8.2 95% CI = 1.12–60.2) and higher blood lactate level at 4 h after ECMO initiation (OR: 2.0 95% CI = 1.23–3.29) were significant and independent risk factors for mortality. Conclusions: Nosocomial infections in medical patients treated with VA-ECMO are very frequent, mostly Gram-negative respiratory infections. Preventive measures could play an important role for these patients.

Background: Evidence has shown that short courses of antibiotic therapy are at least as effective as long courses with better clinical outcomes. CAZ/AVI has demonstrated its clinical efficacy in treating K. pneumoniae-KPC infections. Methods: We conducted an analysis based on the real-life data of our ten years retrospective cohort to assess the cost-effectiveness and cost-utility of a short course of CAZ/AVI plus source control compared to a long course plus source control. A Markov model was structured. Patient transition between health states was modeled, each transition has a probability, and each state has a cost and a utility. Incremental cost-effectiveness ratios (ICERs) were obtained by dividing the difference in costs by the difference in utilities between the two courses. Input parameter uncertainty was investigated through sensitivity analysis. We launched 1000 Monte Carlo simulations by iteratively perturbing variables within estimated variation ranges, obtaining an ICER result for each simulation. Results: In the first model (old appropriate treatment), a short course of treatment was associated with reduced costs per patient per year of €4818.60 and reduced effects (0.10 QALYs), compared to a long course. In the CAZ/AVI model, the short course was associated with increased costs of €1297.9 and with increased effects (0.04 QALYs), resulting in an ICER of €32,317.82 per QALY gained, below the WTP threshold of €40,000. Conclusions: Our findings highlight additional evidence regarding the cost-effectiveness of CAZ/AVI for policy-makers. We outline that CAZ/AVI could be cost-effective compared to old appropriate antibiotic therapies for KPC-Kp BSI.

Bloodstream infections (BSI) are life-threatening complications for onco-hematologic patients. Fluoroquinolones prophylaxis (FQP) was recommended for patients with neutropenia. Later, it was correlated with increased resistance rates among this population and its role became debated. While the role of FQ prophylaxis is still being studied, its cost-effectiveness is also unknown. The objective of this study was to evaluate the costs and effects associated with two alternative strategies (FQP vs. no prophylaxis) for patients with hematological malignancies undergoing allogenic stem cell transplant (HSCT). A decision-tree model was built integrating retrospectively collected data from a single transplant center, part of a tertiary teaching hospital in Northern Italy. Probabilities, costs and effects were considered in the assessment of the two alternative strategies. Probabilities of colonization, BSIs, extended-spectrum beta lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) BSIs and mortality associated with infection, as well as median duration of length of stay (LOS) were calculated based on data collected between 2013 and 2021. The center applied the strategy of FQP between 2013 and 2016, and of no prophylaxis between 2016 and 2021. Data on 326 patients were collected during the considered time period. Overall, the rates of colonization, BSI, KPC/ESBL BSI, and mortality were 6.8% (95% confidence interval (CI) 2.7–13.5), 42% (9.9–81.4) and 20.72 (16.67–25.26), respectively. A mean bed-day cost of 132€ was estimated. Considering no prophylaxis vs. prophylaxis, the difference in costs ranged between additional 33.61 and 80.59€ per patient, whereas the difference in effects ranged between 0.11 and 0.03 life-years (LYs) lost (around 40 and 11 days). Given the small differences in terms of costs and effects between the two strategies, no prophylaxis seems an appropriate choice. Furthermore, this analysis did not consider the broader effect on hospital ecology of multiple doses of FQP, which could provide further support for the strategy of no prophylaxis. Our results suggest that the necessity for FQP in onco-hematologic setting should be determined based on local antibiotic resistance patterns.

Plant-derived extracellular vesicles (EVs) may represent a platform for the delivery of RNA-based vaccines, exploiting their natural membrane envelope to protect and deliver nucleic acids. Here, EVs extracted from orange (Citrus sinensis) juice (oEVs) were investigated as carriers for oral and intranasal SARS-CoV-2 mRNA vaccine. oEVs were efficiently loaded with different mRNA molecules (coding N, subunit 1 and full S proteins) and the mRNA was protected from degrading stress (including RNase and simulated gastric fluid), delivered to target cells and translated into protein. APC cells stimulated with oEVs loaded with mRNAs induced T lymphocyte activation in vitro. The immunization of mice with oEVs loaded with S1 mRNA via different routes of administration including intramuscular, oral and intranasal stimulated a humoral immune response with production of specific IgM and IgG blocking antibodies and a T cell immune response, as suggested by IFN-γ production by spleen lymphocytes stimulated with S peptide. Oral and intranasal administration also triggered the production of specific IgA, the mucosal barrier in the adaptive immune response. In conclusion, plant-derived EVs represent a useful platform for mRNA-based vaccines administered not only parentally but also orally and intranasally.

Background—Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are subject to major risks for bacterial bloodstream infections (BSIs), including emergent multidrug-resistant (MDR) organisms, which still represent the main cause of morbidity and mortality in transplanted patients. Methods: We performed an observational, retrospective, single-center study on patients undergoing allo-HSCT between 2004 and 2020 at the Stem Cell Transplant Unit in Turin to assess the incidence, etiology, and outcomes of BSIs and to explore any risk factors for bacteriaemia. Results: We observed a total of 178 bacterial BSIs in our cohort of 563 patients, resulting in a cumulative incidence of 19.4%, 23.8%, and 28.7% at 30, 100, and 365 days, respectively. Among isolated bacteria, 50.6% were Gram positive (GPB), 41.6% were Gram negative (GNB), and 7.9% were polymicrobial infections. Moreover, BSI occurrence significantly influenced 1-year overall survival. High and very high Disease Risk Index (DRI), an haploidentical donor, and antibacterial prophylaxis were found as results as independent risk factors for bacterial BSI occurrence in multivariate analysis. Conclusions: In our experience, GNB have overwhelmed GPB, and fluoroquinolone prophylaxis has contributed to the emergence of MDR pathogens. Local resistance patterns and patients’ characteristics should therefore be considered for better management of bacteremia in patients receiving an allogeneic HSCT.

Objectives: To explore the Cytomegalovirus (CMV) burden on the long-term post-transplant course in different donor ages, we evaluated the incidence and risk factors for CMV in our kidney-transplanted patients (KTs) with extensive adoption of expanded-criteria donors (ECDs). Methods: Retrospective evaluation of 929 consecutive first KTs (49.5% receiving an organ from a donor ≥ 60 years) performed between 01-2003 and 12-2013. Overall survival was estimated using Kaplan–Meier curves; cumulative incidence function was additionally analyzed to consider the potential role of death with a functioning graft as a competitive event with graft dysfunction and to avoid overestimation. Apart from regular DNAemia monitoring in all patients, prophylaxis was adopted in high-risk groups (D+/R− or recipients of anti-thymocyte globulin induction), with pre-emptive therapy in the remaining groups. Results: CMV incidence was 19.5% (4–34.9% according to serostatus combination: D−/R−, D−/R+, D+/R+, D+/R−). Donor and recipient age, recipient pre-transplant hypertension, DR antigen compatibility, cold ischemia time, and post-transplant early complications, including rejection, urologic and renal artery stenosis, and lower renal function and proteinuria ≥ 0.5 g/day at one year after KT were associated with CMV. CMV determined lower death-censored graft survival (DCGS) (p < 0.01), with a prominent effect in R+ (p < 0.01) and without impact in R− (p = 0.32 in D−/R− and p = 0.006 in D+/R−). Interestingly, CMV occurrence influenced DCGS only in KTs who received grafts from donors < 50 or 50–69 years old (p < 0.01), while it was not significant with older donors (p = 0.07). The analysis of the cumulative incidence of graft loss accounting for death as a competing risk confirmed all these findings. In multivariate analysis, CMV replication/disease in the first year was an independent predictor for DCGS (HR 1.73 [1.3–2.3]). Conclusions: In a large population with extensive ECD adoption, CMV viremia in the first year demonstrates its harmful effect with an independent role for graft loss and significant impact among R+ recipients and KTs with donors < 70 years.

Legionella pneumophila (LP) is one of the main causative agents of community-acquired pneumonia in Europe and its fifth bacterial cause in Italy (4.9%). We conducted a seven year retrospective analysis of LP infection serogroup 1 in Asti, Piedmont, between 2016 and 2022. Patients were included if they tested positive for the Legionella urinary antigen. Clinical, laboratory, and radiologic data were analyzed to describe the risk factors for mortality. Fifty patients with LD were collected, mainly male, with a median age of 69 years. The main comorbidities were cardiovascular diseases (50%), pulmonary diseases (26%), and neurological diseases (12%). The most common clinical presentations were fever, respiratory, gastrointestinal, and neurologic symptoms. Older age (p = 0.004), underlying cardiovascular diseases (p = 0.009), late diagnosis at admission (p = 0.035), and neurological symptoms at diagnosis (p = 0.046) were more common in the non-survivor group. Moreover, a septic-shock presentation or the need for non-invasive ventilation at admission were associated with a higher mortality. No considerable differences in the biochemical data were found between the two groups except for the median neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and PCT value. We did not find any differences in mortality related to the choice of antibiotic regimen. Differences in outcome were associated with the median duration of treatment (p =< 0.001) but not to the choice of antibiotic regimen (mainly levofloxacin or azithromycin). In conclusion, early individuation of the wide spectrum of clinical characteristics of LP infection such as respiratory, cardiac, and neurological manifestations of the patient’s comorbidities, and significant biochemical data should help clinicians flag high risk patients and potentially improve their outcome.

Rapid detection of extended-spectrum-β-lactamase (ESBL) is of paramount importance to accelerate clinical decision-making, optimize antibiotic treatment, and implement adequate infection control measures. This study was aimed at assessing the impact of direct detection of CTX-M ESBL-producers on antimicrobial management of Escherichia coli bloodstream infections over a 2-year period. This study included all E. coli bloodstream infection (BSI) events that were serially processed through a rapid workflow with communication to the clinicians of direct detection of CTX-M ESBL-producers and conventional culture-based workflow. Antimicrobial management was retrospectively analyzed to assess the contribution of the rapid test result. A total of 199 E. coli BSI events with a report of direct detection of CTX-M ESBL production results were included. Of these, 33.7% (n = 67) and 66.3% (n = 132) were reported as positive and negative CTX-M producers, respectively. Detection of CTX-M positive results induced more antibiotic therapy modifications (mainly towards carbapenem-containing regimens, p < 0.01), and antimicrobial susceptibility testing results of CTX-M ESBL-producing E. coli isolates induced more antibiotic escalations towards carbapenem-containing regimens (p < 0.01). Direct detection of CTX-M ESBL-producing E. coli resulted in a remarkable rate of antibiotic optimizations on the same day of blood culture processing. Observing antibiotic management following the availability of antimicrobial susceptibility testing results, additional early optimizations in escalation could probably have been made if the rapid test data had been used. Detection of CTX-M negative results resulted in few therapeutic changes, which could have probably been higher, integrating epidemiological and clinical data.

Antimicrobial resistance (AMR) has become one of the greatest challenges worldwide, hampering the treatment of a plethora of infections. Indeed, the AMR crisis poses a threat to the achievement of the United Nations’ Sustainable Development Goals and, due to its multisectoral character, a holistic approach is needed to tackle this issue. Thus, the investigation of environments beyond the clinic is of utmost importance. Here, we investigated thirteen strains of antimicrobial-resistant Aeromonas isolated from an urban estuary in Brazil. Most strains carried at least one antimicrobial resistance gene and 11 carried at least one heavy metal resistance gene. Noteworthy, four (30.7%) strains carried the blaKPC gene, coding for a carbapenemase. In particular, the whole-genome sequence of Aeromonas hydrophila strain 34SFC-3 was determined, revealing not only the presence of antimicrobial and heavy metal resistance genes but also a versatile virulome repertoire. Mobile genetic elements, including insertion sequences, transposons, integrative conjugative elements, and an IncQ1 plasmid were also detected. Considering the ubiquity of Aeromonas species, their genetic promiscuity, pathogenicity, and intrinsic features to endure environmental stress, our findings reinforce the concept that A. hydrophila truly is a “Jack of all trades’’ that should not be overlooked under the One Health perspective.

Styloid Jugular Nutcracker (SJN, also known as Eagle Jugular Syndrome EJS) derives from a jugular stenosis caused by an abnormal styloid process, compressing the vessel in its superior portion (J3) against the C1 anterior arch. It could be considered a venous vascular variant of Eagle Syndrome (ES). Main clinical features of this ES variant are headache, pulsatile tinnitus and dizziness, possibly related to venous hypertension and impaired cerebral parenchyma drainage. In our opinion, conceptually, it is not the absolute length of the styloid bone that defines its abnormality, but its spatial direction. An elongated bone pointing outward far away from the midline could not compress the vein; vice versa, a short styloid process tightly adherent to the cervical spine could be pathological. To prove this hypothesis, we developed a semi-automatic software that processes CT-Angio images, giving quantitative information about distance and direction of the styloid process in three-dimensional space. We compared eight patients with SJN to a sample of healthy subjects homogeneous for sex and age. Our results suggest that SJN patients have a more vertically directed styloid, and this feature is more important than the absolute distance between the two bony structures. More studies are needed to expand our sample, including patients with the classic and carotid variants of Eagle Syndrome.

Cost-effective remediation is increasingly dependent on high-resolution site characterization (HRSC), which is supposed to be necessary prior to interventions. This paper aims to evaluate the use of low-flow purging and sampling water level data in estimating the horizontal hydraulic conductivity of soils. In a new quali-quantitative view, this procedure can provide much more information and knowledge about the site, reducing time and costs. In case of high heterogeneity along the well screen, the whole procedure, as well as the estimation method, could be less effective and rigorous, with related issues in the purging time. The result showed significant permeability weighted sampling, which could provide different results as the pump position changes along the well screen. The proposed study confirms this phenomenon with field data, demonstrating that the use of multiparameter well logs might be helpful in detecting the behaviour of low-permeability layers and their effects on purging and sampling. A lower correlation between low-flow permeability estimations and LeFranc test results was associated with high heterogeneity along the screen, with a longer purging time. In wells P43, MW08 and MW36, due to the presence of clay layers, results obtained differ for almost one order of magnitude and the purging time increases (by more than 16 min). However, with some precautions prior to the field work, the low-flow purging and sampling procedure could become more representative in a shorter time and provide important hydrogeological parameters such as hydraulic conductivity with many tests and high-resolution related results.

Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB.

Background. In K. pneumoniae KPC (KPC-Kp) bloodstream infections (BSI), INCREMENT CPE score >7, Charlson Comorbidity Index (CCI) ≥3 and septic shock are recognized predictors of mortality, with a possible beneficial effect of combination therapy in seriously ill patients. Materials and Methods. We conducted a ten-year retrospective study including all KPC-Kp BSI in patients ≥18 years of age with the aim to evaluate the characteristics and impact of appropriate empirical therapy, either monotherapy or combination therapy, and targeted therapy on mortality. Appropriate therapy was defined as at least one active antimicrobial agent with in vitro activity against KPC-kp demonstrated by susceptibility testing, administered within 48 h from blood culture collection. Results. The median age of the 435 analyzed patients was 66.09 years (IQR 54.87–73.98). The median CCI was 4. KPC-Kp colonization was present in 324 patients (74.48%). The probable origin of the KPC-Kp BSI was not identified in 136 patients (31.26%), whereas in 120 (27.59%) patients, it was CVC-related, and in 118 (27.13%), it was respiratory. Source control was achieved in 87 patients (72.5%) with CVC-related KPC-Kp BSI. The twenty-eight-day survival was 70.45% for empirical monotherapy, 63.88% for empirical combination therapy and 57.05% for targeted therapy (p = 0.0399). A probable source of KPC-Kp BSI other than urinary, CVC or abdominal [aHR 1.64 (IC 1.15–2.34) p = 0.006] and deferred targeted therapy [HR 1.67 (IC 1.12–2.51), p= 0.013] emerged as predictors of mortality, whereas source control [HR 0.62 (IC 0.44–0.86), p = 0.005] and ceftazidime/avibactam administration in empirical therapy [aHR 0.37 (IC 0.20–0.68) p = 0.002] appeared as protective factors. Discussion. These data underline the importance of source control together with timing appropriateness in the early start of empirical therapy over the choice of monotherapy or combination therapy and the use of ceftazidime/avibactam against KPC-Kp BSI.

The Usutu virus (USUV) has recently attracted the attention of scientists because of its rapid spread across Europe and its growth over the previous seasons in Italy. Here, we describe the first case of USUV infection in Asti, Piedmont region, Italy. The patient remained asymptomatic in the acute phase and during the early follow-up, despite a mild increase in liver enzymes. The prompt diagnosis in this patient was due to positive qualitative PCR for WNV blood-donor screening with negative RT-PCR of WNV and positive USUV-RNA following the confirmation test. Blood-donor screening and transmission risk monitoring are pivotal in following the spread of this Flavivirus in non-endemic countries, due to the high percentage of asymptomatic carriers.

Background. Nocardia is a group of ubiquitous bacteria known to cause opportunistic infections in immunocompromised hosts, including those affected by malignancies and solid-organ or hematopoietic stem cell transplants. Pulmonary involvement, occurring in two-thirds of cases, is the most frequent presentation. Diagnosis might be challenging both because of microbiological technical issues, but also because of the variability of organ involvement and mimicry. Methods. We describe four cases of disseminated nocardiosis caused by N. farcinica observed between September 2021 and November 2021 in immune-compromised hosts presenting with nodular cutaneous lesions that had raised a high degree of clinical suspect and led to microbiological identification through MALDI-TOF MS. Results. Cutaneous involvement is typically reported in immunocompetent hosts with primary cutaneous nocardiosis with multiple forms of manifestation; nonetheless, disseminated nocardiosis rarely involves the skin and subcutaneous tissues, and this occurs as a result of metastatic spread. Our cases were disseminated nocardiosis in which the metastatic cutaneous involvement, even if rare, provided a clue for the diagnosis. Conclusions. The pathomorphosis of disseminated nocardiosis may have changed in the current years with more rapid spread due to advanced immunosuppression. For this reason, after clinical suspicion, the prompt start of an active targeted therapy based on rapid microbiological identification might potentially open the way to hopeful results, even in the most immune-compromised patients.

Real-life experience of molnupiravir treatment is lacking, especially in people hospitalized for underlying diseases not related to COVID-19. We conducted a retrospective analysis regarding molnupiravir therapy in patients with SARS-CoV-2 infection admitted for underlying diseases not associated with COVID-19. Forty-four patients were included. The median age was 79 years (interquartile range [IQR]: 51–93 years), and most males were 57,4%. The median Charlson Comorbidity Index and 4C score were, respectively, 5 (IQR: 3–10) and 9.9 (IQR: 4–12). Moreover, 77.5% of the patients had at least two doses of the anti-SARS-CoV-2 vaccine, although 10.6% had not received any SARS-CoV-2 vaccine. Frequent comorbidities were cardiovascular diseases (68.1%), and diabetes (31.9%), and most admissions were for the acute chronic heart (20.4%) or liver (8.5%) failure. After molnupiravir started, 8 (18.1%) patients developed acute respiratory failure, and five (11.4%) patients died during hospitalisation. Moreover, molnupiravir treatment does not result in a statistically significant change in laboratory markers except for an increase in the monocyte count (p = 0.048, Z = 1.978). Molnupiravir treatment in our analysis was safe and well tolerated. In addition, no patients’ characteristics were found significantly related to hospital mortality or an increase in oxygen support. The efficacy of the molecule remains controversial in large clinical studies, and further studies, including larger populations, are required to fill the gap in this issue.

The reported incidence of COVID-19-associated pulmonary aspergillosis (CAPA) ranges between 2.4% and 35% in intensive care unit (ICU) patients, and awareness in the medical community is rising. We performed a regional retrospective observational study including patients diagnosed with CAPA defined according to the Modified AspICU Dutch/Belgian Mycosis Study Group and CAPA–EECMM, from five different ICUs, admitted between March, 2020 and September, 2021. Forty-five patients were included. The median age was 64 (IQR 60–72), mostly (73%) males. At ICU admission, the median Charlson comorbidity index was 3 (2–5), and the simplified acute physiology score (SAPS)-II score was 42 (31–56). The main underlying diseases were hypertension (46%), diabetes (36%) and pulmonary diseases (15%). CAPA was diagnosed within a median of 17 days (IQR 10–21.75) after symptoms onset and 9 days (IQR 3–11) after ICU admission. The overall 28-day mortality rate was 58%, and at univariate analysis, it was significantly associated with older age (p = 0.009) and SAPS-II score at admission (p = 0.032). The use of immunomodulatory agents, p = 0.061; broad-spectrum antibiotics, p = 0.091; positive culture for Aspergillus on BAL, p = 0.065; and hypertension, p = 0.083, were near reaching statistical significance. None of them were confirmed in multivariate analysis. In critically ill COVID-19 patients, CAPA acquired clinical relevance in terms of incidence and reported mortality. However, the risk between underdiagnosis—in the absence of specific invasive investigations, and with a consequent possible increase in mortality—and over-diagnosis (case identification with galactomannan on broncho-alveolar fluid alone) might be considered. Realistic incidence rates, based on local, real-life epidemiological data, might be helpful in guiding clinicians.

The reactivation of latent Leishmania infection in chronic diseases and immunocompromised hosts is a broad and heterogeneous field in medicine and infectious diseases. We reported one of the first cases of Visceral Leishmaniasis occurring in a Caucasian middle-aged man living in an endemic country (Italy) for Leishmania infantum infection following secukinumab treatment for psoriatic arthritis. The patient was cured with a Liposomal Amphotericin B (L-AmB, 3 mg/Kg on days 1–5, followed by a dose on days 10, 17, 24, 31 and 38) regimen, after which his anti-interleukin 17 treatment was restarted—without recurrence in the follow-up.

At the onset of the SARS-CoV-2 pandemic, individual and social measures were strengthened through restrictive non-pharmaceutical interventions, labelled with the term “lockdown”. In Italy, there were two lockdowns (9 March 2020–3 May 2020 and 3 November 2020–27 March 2021). As part of preventive measures, healthcare workers and the administrative staff population of Policlinico A. Gemelli underwent nasopharyngeal swab tests from 1 March 2020 to 9 February 2022, a long time interval that includes the two aforementioned lockdowns. The population included 8958 people from 1 March 2020 to 31 December 2020; 8981 people from 1 January 2021 to 31 December 2021; and 8981 people from 1 January 2022 to 9 February 2022. We then analysed pseudo-anonymized data, using a retrospective observational approach to evaluate the impact of the lockdown on the incidence of SARS-CoV-2 infections within the population. Given the 14 day contagious period, the swab positivity rate (SPR) among the staff decreased significantly at the end of the first lockdown, every day prior to 18 May 2020, by 0.093 (p < 0.0001, CI = (−0.138–−0.047)). After the fourteenth day post the end of the first lockdown (18 May 2020), the SPR increased daily at a rate of 0.024 (p < 0.0001, 95% CI = (0.013–0.034)). In addition, the SPR appeared to increase significantly every day prior to 17 November 2020 by 0.024 (p < 0.0001, CI = (0.013–0.034)). After the fourteenth day post the start of the second lockdown (17 November 2020), the SPR decreased daily at a rate of 0.039 (p < 0.0001, 95% CI = (−0.050–−0.027)). These data demonstrate that, in our Institution, the lockdowns helped to both protect healthcare workers and maintain adequate standards of care for COVID and non-COVID patients for the duration of the state of emergency in Italy.

Meropenem/vaborbactam (MV) and cefiderocol were recently approved by the Food and Drug Administration and European Medicines Agency and are among the most promising antibacterial in treatment regimens against multi-drug resistant (MDR) gram-negative bacilli. A survey with close-ended questions was proposed to infectious disease (ID) and intensive care unit (ICU) physicians of Piedmont and Valle d’Aosta Region’s hospitals. The aim was to collect data about habits and prescriptions of cefiderocol and MV. Twenty-three physicians (11 ID specialists and 12 anesthesiologists) in 13 Italian hospitals took part in the survey. Both cefiderocol and MV were mostly used as target therapy after a previous treatment failure and after ID specialist consult. The most frequent MDR pathogen in hospitals was Klebsiella pneumoniae carbapenemase-producing bacteria (KPC), followed by P. aeruginosa and A. baumannii. MDRs were more frequently isolated in ICU. In conclusion, cefiderocol was used in empiric regimens when A. baumannii was suspected, while MV was more used in suspect of KPC. MV and cefiderocol can be the first option in empiric treatment for critically ill patients in settings with high risk of MDR. The treatment should then be followed by rapid de-escalation when microbiological results are available.

Candidemia diagnosis is based on the combination of clinical, microbiological and laboratory data. We aimed to evaluate performances and accuracy of (1,3)-β-D-glucan (BDG) at various cut-offs in internal medicine patients. An observational retrospective–prospective study was performed. Patients with at least two determinations of BDG and paired, associated blood cultures within ±48 h were considered. A total of 140 patients were included: 26 with Candida spp. blood-stream infections (BSI) and 114 without candidemia. Patients with candidemia were older and had higher BDG values, need of parenteral nutrition, higher colonization by Candida in more than one site, presence of percutaneous gastrostomy and higher Candida or Charlson scores. BDG maintained the best compromise between sensitivity, specificity and optimal negative predictive value was 150 pg/mL. BDG values at cut-off of 150 pg/mL increase the strength of association between BDG and development of candidemia (Odds Ratio—OR 5.58; CI 2.48–12.53 vs. OR 1.06; CI 1.003–1.008). Analyzing BDG > 150 pg/mL along with Candida score > 2 and Charlson score > 4, the strength of the association amongst BDG, clinical scores and development of candidemia is increased. The overall clinical evaluation with the help of scores that consider BDG values > 150 pg/mL, Candida score > 2 and Charlson score > 4 in combination seems to predict better the need of antifungal empiric treatment.

Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography–tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections.

Eigenfrequencies of a nanobeam with a point mass interacting with a heavy fluid are calculated using Bernoulli-Euler kinematics and consistent nonlocal elasticity model. The proposed approach is applicable to a variety of nanotechnology materials and structures, especially mass nanosensors. Eigenfrequencies are compared with those of local theory and conclusions are drawn. Influence of nonlocal effects, heavy fluid interaction and added point mass on dynamic responses is analyzed and the results are documented. Size phenomena are noted and discussed.

West Nile virus (WNV) infection is a reemerging zoonosis recently provoking significant outbreaks throughout Europe. During the summer of 2018, the number of WNV infections rose with a peak of new diagnoses of West Nile neuro-invasive disease (WNND). Most of the Italian cases were clustered in the Po River Valley. We present a case series of nine patients with WNV infection admitted to the Cardinal Massaia Hospital from 30 August 2018 to 1 October 2018. Demographic, immunovirological, clinical and therapeutic data are shown, and a report on clinical sequelae from the subsequent follow-up in patients with WNV and WNND. We showed the clinical, radiological and biochemical characteristics of WNV-infected patients. The risk factors and the clinical presentation of WNV in most patients in our case series were typical of that described in the literature, although, despite the high morbidity and mortality of WNND, we showed survival of 100% and long-term sequelae in only three patients. Environmental conditions may be essential in WNV outbreaks, and WNND can be clinically neurological multiform. Our long-lasting follow-up with clinical or radiological monitoring confirmed the morbidity of long-term neurological sequelae after WNND. Further studies are needed to investigate the epidemiology and physiopathology of bacterial superinfections after WNV infection.

Candida auris is an emerging healthcare-associated infection that can easily cause dissemination in hospitals through colonizing the skin and contaminating environmental surfaces, especially in Intensive Care Units (ICU). Difficulties with identification of this organism, uncertainty about routes of transmission and antifungals resistance have impacted significantly outbreak detection and management. Here, we describe our experience with colonization/infection of C. auris among critically ill patients, admitted to a referral ICU of a University Hospital, in a transitional period (July 2021–March 2022) between management of non-COVID-19 and COVID-19 patients due to the reconversion of the ICU between two waves. A total of 8 patients presented colonization from C. auris, and two of them developed invasive infection from C. auris. The fungal pathogen was cultured from different sites: the skin (7 isolates), urine (2), respiratory tract (1), blood (1). The median time from admission to first detection is 24 days with 100% of patients requiring mechanical ventilation. All 8 patients received broad-spectrum antibiotic therapy for bacterial infections before identification of C. auris; 62.5% of the patients had prior antifungal exposure; 87.5% received steroids; 37.5% patients used immunomodulatory; and 75% had severe COVID-19 illness prior to C. auris identification. Only two cases (25%) were treated with antifungals as C. auris infections (1 patient for suspected UTI; 1 patient with candidemia). Infection control measures, including rapid microbiological identification, contact isolation, screening of contacts, antisepsis of colonized patients, dedicated equipment, cleaning and disinfection of the environment and subsequent follow-up sampling, remain essential in critically ill patients. Our experience highlights the importance of establishing a multidisciplinary model and bundling of practices for preventing C. auris’ spread.

In this paper, we use the methods of networks science to analyse the transaction networks of tokens running on the Ethereum blockchain. We start with a deep dive on four of them: Ampleforth (AMP), Basic Attention Token (BAT), Dai (DAI) and Uniswap (UNI). We study two types of blockchain addresses, smart contracts (SC), which run code, and externally owned accounts (EOA), run by human users, or off-chain code, with the corresponding private keys. We use preferential attachment and network dismantling strategies to evaluate their importance for the network structure. Subsequently, we expand our view to all ERC-20 tokens issued on the Ethereum network. We first study multilayered networks composed of Ether (ETH) and individual tokens using a dismantling approach to assess how the deconstruction starting from one network affects the other. Finally, we analyse the Ether network and Ethereum-based token networks to find similarities between sets of high-degree nodes. For this purpose, we use both the traditional Jaccard Index and a new metric that we introduce, the Ordered Jaccard Index (OJI), which considers the order of the elements in the two sets that are compared. Our findings suggest that smart contracts and exchange-related addresses play a structural role in transaction networks both in DeFi and Ethereum. The presence in the network of nodes associated to addresses of smart contracts and exchanges is positively correlated with the success of the token network measured in terms of network size and market capitalisation. These nodes play a fundamental role in the centralisation of the supposedly decentralised finance (DeFi) ecosystem: without them, their networks would quickly collapse.

Considering the growing prevalence of carbapenem-resistant Gram-negative bacteria (CR-GNB) bloodstream infection (BSI) in intensive care units (ICUs), the identification of specific risk factors and the development of a predictive model allowing for the early identification of patients at risk for CR-Klebsiella pneumoniae, Acinetobacter baumannii or Pseudomonas aeruginosa are essential. In this retrospective case–control study including all consecutive patients showing an episode of BSI in the ICUs of a university hospital in Italy in the period January–December 2016, patients with blood culture positive for CR-GNB pathogens and for any other bacteria were compared. A total of 106 patients and 158 episodes of BSI were identified. CR-GNBs induced BSI in 49 patients (46%) and 58 episodes (37%). Prognosis score and disease severity at admission, parenteral nutrition, cardiovascular surgery prior to admission to ICU, the presence of sepsis and septic shock, ventilation-associated pneumonia and colonization of the urinary or intestinal tract were statistically significant in the univariate analysis. The duration of ventilation and mortality at 28 days were significantly higher among CR-GNB cases. The prognostic model based on age, presence of sepsis, previous cardiovascular surgery, SAPS II, rectal colonization and invasive respiratory infection from the same pathogen showed a C-index of 89.6%. The identified risk factors are in line with the international literature. The proposal prognostic model seems easy to use and shows excellent performance but requires further studies to be validated.

End-stage liver disease patients undergoing liver transplantation are prone to develop numerous infectious complications because of immunosuppression, surgical interventions, and malnutrition. Infections in transplant recipients account for the main cause of mortality and morbidity with rates of up to 80%. The challenges faced in the early post-transplant period tend to be linked to transplant procedures and nosocomial infections commonly in bloodstream, surgical, and intra-abdominal sites. Viral infections represent an additional complication of immunosuppression; they can be donor-derived, reactivated from a latent virus, nosocomial or community-acquired. Bacterial and viral infections in solid organ transplantation are managed by prophylaxis, multi-drug resistant screening, risk assessment, vaccination, infection control and antimicrobial stewardship. The aim of this review was to discuss the epidemiology of bacterial and viral infections in liver transplants, infection control issues, as well as surgical frontiers of ex situ liver perfusion.

The pandemic caused by the COVID-19 virus has required major adjustments to healthcare systems, especially to infection control and antimicrobial stewardship. The objective of this study was to describe the incidence of multidrug-resistant (MDR) hospital-acquired infections (HAIs) and antibiotic consumption during the three waves of COVID-19 and to compare it to the period before the outbreak at Molinette Hospital, located in the City of Health and Sciences, a 1200-bed teaching hospital with surgical, medical, and intensive care units. We demonstrated an increase in MDR infections: particularly in K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), A. baumannii, and MRSA. Fluoroquinolone use showed a significant increasing trend in the pre-COVID period but saw a significant reduction in the COVID period. The use of fourth- and fifth-generation cephalosporins and piperacillin–tazobactam increased at the beginning of the COVID period. Our findings support the need for restoring stewardship and infection control practices, specifically source control, hygiene, and management of invasive devices. In addition, our data reveal the need for improved microbiological diagnosis to guide appropriate treatment and prompt infection control during pandemics. Despite the infection control practices in place during the COVID-19 pandemic, invasive procedures in critically ill patients and poor source control still increase the risk of HAIs caused by MDR organisms.

Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD’s impact on AFU therapy. The aim of this study was to analyze if VD pathway-related polymorphisms may influence voriconazole (VRC), itraconazole (ITC), and posaconazole (PSC) drug concentrations in order to identify patients with the highest probability of response and toxicity. Allelic discrimination was performed through real-time PCR, whereas drug concentrations were through liquid chromatography. A total of 636 samples of AFU-treated patients were included in the analysis. Concerning VRC, concentrations higher than the 1000 ng/mL efficacy cut-off value were predicted by Caucasian ethnicity, CYP24A1 3999, and CYP27B1 + 2838 polymorphisms, whereas levels higher than the 5000 ng/mL toxicity value by Caucasian, female sex, e.v. administration, and GC 1296. Considering PSC, concentrations higher than the 700 ng/mL efficacy cut-off value were predicted by VDR Cdx2, CYP27B1 − 1260, and GC 1296. Finally, for ITC, VDR BsmI was the only predictor of drug exposure higher than the 500 ng/mL efficacy cut-off value, whereas female sex, CYP27B1 − 1260, and VDR TaqI remained in the final regression model related to concentrations higher than the 1000 ng/mL toxicity-associated cut-off value. This is the first study reporting the influence of VD pathway-related gene SNPs on AFU exposures, efficacy, and toxicity.

Eagle Syndrome is an underestimated syndrome with broad and often unspecific signs and symptoms. Both the neuropathic and vascular patterns need a thorough investigation in terms of all their clinical and radiological aspects. A positional/dynamic study is mandatory in the case of suspicion of Eagle Syndrome due to the strong influence of head and neck positions. This work aims to propose a new virtual technique able to predict conflicts between the styloid process and neck vascular structures.