Inferior vena cava distensibility during pressure support ventilation: a prospective study evaluating interchangeability of subcostal and trans­hepatic views, with both M­mode and automatic border tracing.

The Inferior Vena Cava (IVC) is commonly utilized to evaluate fluid status in the Intensive Care Unit (ICU),with more recent emphasis on the study of venous congestion. It is predominantly measured via subcostal approach (SC) or trans-hepatic (TH) views, and automated border tracking (ABT) software has been introduced to facilitate its assessment. Prospective observational study on patients ventilated in pressure support ventilation (PSV) with 2 × 2 factorial design. Primary outcome was to evaluate interchangeability of measurements of the IVC and the distensibility index (DI) obtained using both M-mode and ABT, across both SC and TH. Statistical analyses comprised Bland-Altman assessments for mean bias, limits of agreement (LoA), and the Spearman correlation coefficients. IVC visualization was 100% successful via SC, while TH view was unattainable in 17.4% of cases. As compared to the M-mode, the IVC-DI obtained through ABT approach showed divergences in both SC (mean bias 5.9%, LoA -18.4% to 30.2%, ICC = 0.52) and TH window (mean bias 6.2%, LoA -8.0% to 20.4%, ICC = 0.67). When comparing the IVC-DI measures obtained in the two anatomical sites, accuracy improved with a mean bias of 1.9% (M-mode) and 1.1% (ABT), but LoA remained wide (M-mode: -13.7% to 17.5%; AI: -19.6% to 21.9%). Correlation was generally suboptimal (r = 0.43 to 0.60). In PSV ventilated patients, we found that IVC-DI calculated with M-mode is not interchangeable with ABT measurements. Moreover, the IVC-DI gathered from SC or TH view produces not comparable results, mainly in terms of precision.

Estimation of the transpulmonary pressure from the central venous pressure in mechanically ventilated patients.

Transpulmonary pressure (PL) calculation requires esophageal pressure (PES) as a surrogate of pleural pressure (Ppl), but its calibration is a cumbersome technique. Central venous pressure (CVP) swings may reflect tidal variations in Ppl and could be used instead of PES, but the interpretation of CVP waveforms could be difficult due to superposition of heartbeat-induced pressure changes. Thus, we developed a digital filter able to remove the cardiac noise to obtain a filtered CVP (f-CVP). The aim of the study was to evaluate the accuracy of CVP and filtered CVP swings (ΔCVP and Δf-CVP, respectively) in estimating esophageal respiratory swings (ΔPES) and compare PL calculated with CVP, f-CVP and PES; then we tested the diagnostic accuracy of the f-CVP method to identify unsafe high PL levels, defined as PL>10 cmH2O. Twenty patients with acute respiratory failure (defined as PaO2/FiO2 ratio below 200 mmHg) treated with invasive mechanical ventilation and monitored with an esophageal balloon and central venous catheter were enrolled prospectively. For each patient a recording session at baseline was performed, repeated if a modification in ventilatory settings occurred. PES, CVP and airway pressure during an end-inspiratory and -expiratory pause were simultaneously recorded; CVP, f-CVP and PES waveforms were analyzed off-line and used to calculate transpulmonary pressure (PLCVP, PLf-CVP, PLPES, respectively). Δf-CVP correlated better than ΔCVP with ΔPES (r = 0.8, p = 0.001 vs. r = 0.08, p = 0.73), with a lower bias in Bland Altman analysis in favor of PLf-CVP (mean bias - 0.16, Limits of Agreement (LoA) -1.31, 0.98 cmH2O vs. mean bias - 0.79, LoA - 3.14, 1.55 cmH2O). Both PLf-CVP and PLCVP correlated well with PLPES (r = 0.98, p < 0.001 vs. r = 0.94, p < 0.001), again with a lower bias in Bland Altman analysis in favor of PLf-CVP (0.15, LoA - 0.95, 1.26 cmH2O vs. 0.80, LoA - 1.51, 3.12, cmH2O). PLf-CVP discriminated high PL value with an area under the receiver operating characteristic curve 0.99 (standard deviation, SD, 0.02) (AUC difference = 0.01 [-0.024; 0.05], p = 0.48). In mechanically ventilated patients with acute respiratory failure, the digital filtered CVP estimated ΔPES and PL obtained from digital filtered CVP represented a reliable value of standard PL measured with the esophageal method and could identify patients with non-protective ventilation settings.

Inferior vena cava distensibility from subcostal and trans-hepatic imaging using both M-mode or artificial intelligence: a prospective study on mechanically ventilated patients.

BACKGROUND: Variation of inferior vena cava (IVC) is used to predict fluid-responsiveness, but the IVC visualization with standard sagittal approach (SC, subcostal) cannot be always achieved. In such cases, coronal trans-hepatic (TH) window may offer an alternative, but the interchangeability of IVC measurements in SC and TH is not fully established. Furthermore, artificial intelligence (AI) with automated border detection may be of clinical value but it needs validation. METHODS: Prospective observational validation study in mechanically ventilated patients with pressure-controlled mode. Primary outcome was the IVC distensibility (IVC-DI) in SC and TH imaging, with measurements taken both in M-Mode or with AI software. We calculated mean bias, limits of agreement (LoA), and intra-class correlation (ICC) coefficient. RESULTS: Thirty-three patients were included. Feasibility rate was 87.9% and 81.8% for SC and TH visualization, respectively. Comparing imaging from the same anatomical site acquired with different modalities (M-Mode vs AI), we found the following IVC-DI differences: (1) SC: mean bias - 3.1%, LoA [- 20.1; 13.9], ICC = 0.65; (2) TH: mean bias - 2.0%, LoA [- 19.3; 15.4], ICC = 0.65. When comparing the results obtained from the same modality but from different sites (SC vs TH), IVC-DI differences were: (3) M-Mode: mean bias 1.1%, LoA [- 6.9; 9.1], ICC = 0.54; (4) AI: mean bias 2.0%, LoA [- 25.7; 29.7], ICC = 0.32. CONCLUSIONS: In patients mechanically ventilated, AI software shows good accuracy (modest overestimation) and moderate correlation as compared to M-mode assessment of IVC-DI, both for SC and TH windows. However, precision seems suboptimal with wide LoA. The comparison of M-Mode or AI between different sites yields similar results but with weaker correlation. Trial registration Reference protocol: 53/2022/PO, approved on 21/03/2022.

An Observational Study to Develop a Predictive Model for Bacterial Pneumonia Diagnosis in Severe COVID-19 Patients-C19-PNEUMOSCORE.

In COVID-19 patients, antibiotics overuse is still an issue. A predictive scoring model for the diagnosis of bacterial pneumonia at intensive care unit (ICU) admission would be a useful stewardship tool. We performed a multicenter observational study including 331 COVID-19 patients requiring invasive mechanical ventilation at ICU admission; 179 patients with bacterial pneumonia; and 152 displaying negative lower-respiratory samplings. A multivariable logistic regression model was built to identify predictors of pulmonary co-infections, and a composite risk score was developed using ß-coefficients. We identified seven variables as predictors of bacterial pneumonia: vaccination status (OR 7.01; 95% CI, 1.73-28.39); chronic kidney disease (OR 3.16; 95% CI, 1.15-8.71); pre-ICU hospital length of stay ≥ 5 days (OR 1.94; 95% CI, 1.11-3.4); neutrophils ≥ 9.41 × 109/L (OR 1.96; 95% CI, 1.16-3.30); procalcitonin ≥ 0.2 ng/mL (OR 5.09; 95% CI, 2.93-8.84); C-reactive protein ≥ 107.6 mg/L (OR 1.99; 95% CI, 1.15-3.46); and Brixia chest X-ray score ≥ 9 (OR 2.03; 95% CI, 1.19-3.45). A predictive score (C19-PNEUMOSCORE), ranging from 0 to 9, was obtained by assigning one point to each variable, except from procalcitonin and vaccine status, which gained two points each. At a cut-off of ≥3, the model exhibited a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 84.9%, 55.9%, 69.4%, 75.9%, and 71.6%, respectively. C19-PNEUMOSCORE may be an easy-to-use bedside composite tool for the early identification of severe COVID-19 patients with pulmonary bacterial co-infection at ICU admission. Its implementation may help clinicians to optimize antibiotics administration in this setting.

MR-proADM as Prognostic Factor of Outcome in COVID-19 Patients.

BACKGROUND: Serum mid-regional proadrenomedullin (MR-proADM) has emerged as a marker of organ failure (mainly lungs and kidneys) and poor prognosis in patients admitted to intensive care (IC); some reports also suggest it and other markers, such as Krebs von den Lungen-6 (KL-6) and interleukin-6 (IL-6), as a prognostic biomarker of COVID-19. The aim of the study was to evaluate the performance MR-proADM in hospitalized COVID-19 patients for predicting in-hospital mortality and need for non-invasive or invasive respiratory support. METHODS: We enrolled 74 patients hospitalized in the COVID Unit of Siena Hospital from March to May 2020, for whom serum samples were available on admission for assay of MR-proADM, KL-6 and IL-6. Demographic data, comorbidities, medical history and clinical laboratory data on days 1-3 of admission and Simplified Acute Physiology Score and Simplified Organ Failure Assessment scores calculated at day 1 were collected retrospectively, as well as mortality and IC admission data. RESULTS: 12 patients died in hospital (16%) and 14 patients were admitted to IC (19%). Serum concentrations of MR-proADM on admission and on day 1 were higher among non-survivors than among survivors (p = 0.015 and p = 0.045, respectively), while those on day 3 were not significantly different. Patients needing respiratory support had higher MR-proADM concentrations on admission than the others (p = 0.046), and those requiring invasive mechanical ventilation had higher MR-proADM on day 1 (p = 0.017). Serum concentrations of KL-6 and IL-6 were significantly higher in non-survivors (p = 0.03 and p = 0.004, respectively). ROC curve analysis showed that serum MR-proADM on day 1 had the best accuracy in predicting death and/or IC admission (AUC = 0.9583, p = 0.0006); the combination of all three biomarkers further improved the accuracy of prediction of death or IC admission (AUC = 0.9793; p = 0.00004). CONCLUSIONS: Our data sustain the potential of serum MR-proADM as a reliable prognostic biomarker of hospitalized COVID-19 patients and confirms the utility of the three markers in the management and risk stratification of hospitalized patients. The markers are collected mini-invasively and are quick to analyze and cost-effective.

Rapid Decrease in Fluoroquinolones Consumption following Implementation of a Simple Antimicrobial Stewardship Bundled Intervention in a University Hospital during the COVID-19 Pandemic.

Fluoroquinolones (FQs) represent an class of antibiotics of medical importance, but their use has been restricted due to their ecologic impact and associated side effects. The reduction of FQs use is an important goal of antimicrobial stewardship programs (ASP). This work describes an ASP focused on overall antibiotics and FQs consumption reduction. From January 2021, an ASP was implemented in a 700-bed teaching hospital. The ASP was based on: (i) antibiotics consumption monitoring system (DDD/100 bed days); (ii) mandatory antibiotic prescription-motivation (using a dedicated informatic format) with the goal of >75% of motivated prescriptions; and (iii) data feedback and training on FQs use indications. We evaluated the impact of the intervention on overall systemic antibiotics and FQs consumption according to the objectives posed by Italian PNCAR (National Action Plan on Antimicrobial Resistance). A decrease of 6.6% in antibiotic use was observed (2019 vs. 2021). Notably, the FQs consumption fell by 48.3% from 7.1 DDD/100 bd in 2019 to 3.7 DDD/100 bd in 2021 (p < 0.001). After six months of mandatory antibiotic prescription-indication, all units achieved the target set. The study suggests that a simple, bundled ASP intervention can be rapidly effective obtaining the objectives of PNCAR on the reduction of overall antibiotics and FQs consumption.

Potential nutritional and pharmacological treatment of glycocalyx alterations during sepsis.

During sepsis, a combination of pathophysiological insults disrupts the glycocalyx. The thickness of the glycocalyx is correlated with parameters of disease severity, making it a potential new and independent target for therapeutic strategies in sepsis. The aim of this review was to examine potential beneficial effects of nutritional and pharmacological measures on glycocalyx alterations during sepsis and their timing.

Regional Cerebral Oxygen Saturation to Predict Favorable Outcome in Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to investigate the role of regional cerebral oxygen saturation (rSO2) in predicting survival and neurologic outcomes after extracorporeal cardiopulmonary resuscitation (ECPR). DESIGN: The study authors performed a systematic review and meta-analysis of all available literature. SETTING: The authors searched relevant databases (Pubmed, Medline, Embase) for studies measuring precannulation rSO2 in patients undergoing ECPR and reporting mortality and/or neurologic outcomes. PARTICIPANTS: The authors included both in-hospital and out-of-hospital cardiac arrest patients receiving ECPR. They identified 3 observational studies, including 245 adult patients. INTERVENTIONS: The authors compared patients with a low precannulation rSO2 (≤15% or 16%) versus patients with a high (>15% or 16%) precannulation rSO2. In addition, the authors carried out subgroup analyses on out-of-hospital cardiac arrest (OHCA) patients. MEASUREMENTS AND MAIN RESULTS: A high precannulation rSO2 was associated with an overall reduced risk of mortality in ECPR recipients (98 out of 151 patients [64.9%] in the high rSO2 group, v 87 out of 94 patients [92.5%] in the low rSO2 group, risk differences [RD] -0.30; 95% CI -0.47 to -0.14), and in OHCA (78 out of 121 patients [64.5%] v 82 out of 89 patients [92.1%], RD 0.30; 95% CI -0.48 to -0.12). A high precannulation rSO2 also was associated with a significantly better neurologic outcome in the overall population (42 out of 151 patients [27.8%] v 2 out of 94 patients [2.12%], RD 0.22; 95% CI 0.13-0.31), and in OHCA patients (33 out of 121 patients [27.3%] v 2 out of 89 patients [2.25%] RD 0.21; 95% CI 0.11-0.30). CONCLUSIONS: A low rSO2 before starting ECPR could be a predictor of mortality and survival with poor neurologic outcomes.

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study.

BACKGROUND: Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. METHODS: This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. RESULTS: Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p < 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO2 ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p < 0.001 and p = 0.004). CONCLUSIONS: DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021).

Uric Acid Expression in Carotid Atherosclerotic Plaque and Serum Uric Acid Are Associated With Cerebrovascular Events.

BACKGROUND: Uric acid (UA) concentration within carotid plaque and its association with cerebrovascular events have not been detected or quantified. Systemically, serum UA is a marker of inflammation and risk factor for atherosclerosis. However, its association with carotid plaque instability and stroke pathogenesis remains unclear. In patients undergoing carotid endarterectomy, we aimed to determine whether UA is present differentially in symptomatic versus asymptomatic carotid plaques and whether serum UA is associated with cerebrovascular symptoms (stroke, transient ischemic attack, or amaurosis fugax). METHODS: Carotid atherosclerotic plaques were collected during carotid endarterectomy. The presence of UA was assessed using Gomori methenamine silver staining as well as anti-UA immunohistochemical staining and its quantity measured using an enzymatic colorimetric assay. Clinical information was obtained through a retrospective review of data. RESULTS: UA was more commonly detected in symptomatic (n=23) compared with asymptomatic (n=9) carotid plaques by Gomori methenamine silver (20 [86.9%] versus 2 [22.2%]; P=0.001) and anti-UA immunohistochemistry (16 [69.5%] versus 1 [11.1%]; P=0.004). UA concentration was higher in symptomatic rather than asymptomatic plaques (25.1 [9.5] versus 17.9 [3.8] µg/g; P=0.021). Before carotid endarterectomy, serum UA levels were higher in symptomatic (n=341) compared with asymptomatic (n=146) patients (5.9 [interquartile range, 4.6-6.9] mg/dL versus 5.2 [interquartile range, 4.6-6.2] mg/dL; P=0.009). CONCLUSIONS: The current study supports a potential role of UA as a potential tissue participant and a systemic biomarker in the pathogenesis of carotid atherosclerosis. UA may provide a mechanistic explanation for plaque instability and subsequent ischemic cerebrovascular events.

Omicron Infection Evokes Cross-Protection against SARS-CoV-2 Variants in Vaccinees.

Due to the rapid global spread of the Omicron (B.1.1.529) variant, efforts to scale up COVID-19 booster vaccination have been improved, especially in light of the increasing evidence of reduced neutralizing antibody (NT Ab) over time in vaccinated subjects. In this study, neutralizing antibody responses against the Wild-Type, Delta, and Omicron strains were evaluated among vaccinees, both infected with Omicron or uninfected, and non-vaccinated subjects infected with Omicron. The aim of the study was to compare the cross-protective humoral response to the variant strains induced by vaccination and/or Omicron infection. The results showed a significant difference in the neutralizing antibody response between the vaccinees and the Omicron-infected vaccinated subjects against the three tested strains (p < 0.001), confirming the booster effect of the Omicron infection in the vaccinees. By contrast, Omicron infection only did not enhance the antibody response to the other variants, indicating a lack of cross-protection. These results suggest the importance of updating the current formulation of the SARS-CoV-2 vaccine to protect people against the Omicron subvariants. A specific Omicron vaccine, administered as a booster for the previously adopted mRNA vaccines, may protect against a wider range of SARS-CoV-2 variants. However, it is unlikely that the Omicron vaccine alone would be able to protect non-vaccinated subjects against other circulating variants.

Overview of Anti-SARS-CoV-2 Immune Response Six Months after BNT162b2 mRNA Vaccine.

BACKGROUND: We have designed a prospective study aiming to monitor the immune response in 178 health care workers six months after BNT162b2 mRNA vaccination. METHODS: The humoral immune response of all subjects was evaluated by chemiluminescence (CMIA); in 60 serum samples, a live virus-based neutralization assay was also tested. Moreover, 6 months after vaccination, B- and T-cell subsets from 20 subjects were observed by FACS analysis after restimulation with the trimeric SARS-CoV-2 Spike protein as an antigen, thus mimicking reinfection in vitro. RESULTS: A significant decrease of circulating IgG levels and neutralizing antibodies over time were observed. Moreover, six months after vaccination, a variable T-cell immune response after in vitro antigen stimulation of PBMC was observed. On the contrary, the analysis of B-cell response showed a shift from unswitched to switched memory B-cells and an increase of Th17 cells. CONCLUSIONS: Although the variability of the CD4+ and CD8+ immune response and an antibody decline was observed among vaccinated subjects, the increase of switched memory B-cells and Th17 cells, correlating with the presence of neutralizing antibodies, opened the debate on the correct timing of vaccination.

Hyperammonemia during treatment with valproate in critically ill patients.

INTRODUCTION: Hyperammonemia (HA) is a potential side-effect of valproate (VPA) treatment, which has been described during long-term administration. The aim of this study was to evaluate the incidence, the impact and the risk factors of HA in critically ill patients. METHODS: We reviewed the data of all adult patients treated in our mixed 35-bed Department of Intensive Care over a 12-year period (2004-2015) who: a) were treated with VPA for more than 72 h and b) had at least one measurement of ammonium and VPA levels during the ICU stay; patients with Child-Pugh C liver cirrhosis were excluded. HA was defined as ammonium levels above 60 µg/dl. RESULTS: Of a total of 2640 patients treated with VPA, 319 patients met the inclusion criteria (median age 64 years; male gender 55%); 78% of them were admitted for neurological reasons and ICU mortality was 30%. Median ammonium levels were 88 [63-118] µg/dl. HA was found in 245 (77%) patients. For those patients with HA, median time from start of VPA therapy to HA was 3 [2-5] days. In a multivariable analysis, high VPA serum levels, mechanical ventilation and sepsis were independently associated with HA during VPA therapy. In 98/243 (40%) of HA patients, VPA was interrupted; VPA interruption was more frequent in patients with ammonium levels > 100 µg/dl than others (p = 0.001). HA was not an independent predictor of ICU mortality or poor neurological outcome. CONCLUSIONS: In this study, HA was a common finding during treatment with VPA in acutely ill patients. VPA levels, sepsis and mechanical ventilation were risk factors for HA. Hyperammonemia did not influence patients' outcome.

Biomarkers Predict In-Hospital Major Adverse Cardiac Events in COVID-19 Patients: A Multicenter International Study.

BACKGROUND: The COVID-19 pandemic carries a high burden of morbidity and mortality worldwide. We aimed to identify possible predictors of in-hospital major cardiovascular (CV) events in COVID-19. METHODS: We retrospectively included patients hospitalized for COVID-19 from 10 centers. Clinical, biochemical, electrocardiographic, and imaging data at admission and medications were collected. Primary endpoint was a composite of in-hospital CV death, acute heart failure (AHF), acute myocarditis, arrhythmias, acute coronary syndromes (ACS), cardiocirculatory arrest, and pulmonary embolism (PE). RESULTS: Of the 748 patients included, 141(19%) reached the set endpoint: 49 (7%) CV death, 15 (2%) acute myocarditis, 32 (4%) sustained-supraventricular or ventricular arrhythmias, 14 (2%) cardiocirculatory arrest, 8 (1%) ACS, 41 (5%) AHF, and 39 (5%) PE. Patients with CV events had higher age, body temperature, creatinine, high-sensitivity troponin, white blood cells, and platelet counts at admission and were more likely to have systemic hypertension, renal failure (creatinine ≥ 1.25 mg/dL), chronic obstructive pulmonary disease, atrial fibrillation, and cardiomyopathy. On univariate and multivariate analysis, troponin and renal failure were associated with the composite endpoint. Kaplan-Meier analysis showed a clear divergence of in-hospital composite event-free survival stratified according to median troponin value and the presence of renal failure (Log rank p < 0.001). CONCLUSIONS: Our findings, derived from a multicenter data collection study, suggest the routine use of biomarkers, such as cardiac troponin and serum creatinine, for in-hospital prediction of CV events in patients with COVID-19.

Fibrous heart valve leaflet substrate with native-mimicked morphology.

Tissue-engineered heart valves are a promising alternative solution to prosthetic valves. However, long-term functionalities of tissue-engineered heart valves depend on the ability to mimic the trilayered, oriented structure of native heart valve leaflets. In this study, using electrospinning, we developed trilayered microfibrous leaflet substrates with morphological characteristics similar to native leaflets. The substrates were implanted subcutaneously in rats to study the effect of their trilayered oriented structure on in vivo tissue engineering. The tissue constructs showed a well-defined structure, with a circumferentially oriented layer, a randomly oriented layer and a radially oriented layer. The extracellular matrix, produced during in vivo tissue engineering, consisted of collagen, glycosaminoglycans, and elastin, all major components of native leaflets. Moreover, the anisotropic tensile properties of the constructs were sufficient to bear the valvular physiological load. Finally, the expression of vimentin and α-smooth muscle actin, at the gene and protein level, was detected in the residing cells, revealing their growing state and their transdifferentiation to myofibroblasts. Our data support a critical role for the trilayered structure and anisotropic properties in functional leaflet tissue constructs, and indicate that the leaflet substrates have the potential for the development of valve scaffolds for heart valve replacements.

Hyperimmune plasma in three immuno-deficient patients affected by non-severe, prolonged COVID-19: a single-center experience.

BACKGROUND: Convalescent plasma (CP) and hyperimmune plasma (HP) are passive immunotherapies consisting in the infusion of plasma from recovered people into infected patients. Following pre-existing evidence in many other viral diseases, such as SARS, MERS and Ebola, CP and HP have also been proposed for the treatment of COVID-19. Nevertheless, due to the lack of large, well-designed, clinical trials, no clear-cut guidelines exist about what subtype of patient CP and HP should be administered to. CASE PRESENTATION: We have reported the cases of 3 patients, all immunosuppressed and affected by non-severe, prolonged COVID-19. They were treated with HP, whose neutralizing titer was higher than 1/80. The first patient was a 55-year-old male, who had undergone lung transplant. He was under therapy with Tacrolimus and developed non-neutralizing antibodies against SARS-CoV2. The second patient was a 77-year-old female, affected by follicular lymphoma. She had tested positive for SARS-CoV2 after 6 months. The third was a 60-year-old patient, affected by chronic leukemia. He did not develop antibodies after 2-month disease. All 3 patients received HP and had tested negative for SARS-CoV2 within 2 weeks. CONCLUSION: Despite encouraging initial data, no strong evidence exist in support of CP and HP to treat COVID-19. In our experience, although limited due to the reduced number of patients, we found a good safety and efficacy of HP in 3 immuno-deficient subjects. Further data are needed in order to assess whether this subtype of patients may particularly benefit from passive immunization.

Association between preoperative evaluation with lung ultrasound and outcome in frail elderly patients undergoing orthopedic surgery for hip fractures: study protocol for an Italian multicenter observational prospective study (LUSHIP).

BACKGROUND: Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of "indirect" and "direct" cardiac and pulmonary lung ultrasound signs. METHODS: LUSHIP is an Italian multicenter prospective observational study. Patients will be recruited on a nation-wide scale in the 12 participating centers. Patients aged > 65 years undergoing spinal anesthesia for hip fracture fixation will be enrolled. A lung ultrasound score (LUS) will be generated based on the examination of six areas of each lung and ascribing to each area one of the four recognized aeration patterns-each of which is assigned a subscore of 0, 1, 2, or 3. Thus, the total score will have the potential to range from a minimum of 0 to a maximum of 36. The association between 30-day postoperative complications of cardiac and/or pulmonary origin and the overall mortality will be studied. Considering the fact that cardiac complications in patients undergoing hip surgery occur in approx. 30% of cases, to achieve 80% statistical power, we will need a sample size of 877 patients considering a relative risk of 1.5. CONCLUSIONS: Lung ultrasound (LU), as a tool within the anesthesiologist's armamentarium, is becoming increasingly widespread, and its use in the preoperative setting is also starting to become more common. Should the study demonstrate the ability of LU to predict postoperative cardiac and pulmonary complications in hip fracture patients, a randomized clinical trial will be designed with the scope of improving patient outcome. Trial registration ClinicalTrials.gov, NCT04074876. Registered on August 30, 2019.

Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression.

Background and Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors. Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured. Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P<0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P<0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels (P=0.010, r=−0.30) and directly with circulating uric acid levels (P<0.001, r=0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P<0.001). Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.