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Background MessengerRNA (mRNA) COVID–19 vaccination has been associated with a higher–than–expected occurrence of acute myocarditis. Scarce information is available on mid–term prognosis and changes in cardiac function, volumes, and tissue characterization on cardiac magnetic resonance (CMR). Methods Retrospective, multicenter study including patients with a definite diagnosis of acute myocarditis within 30 days from mRNA COVID–19 vaccination. The diagnosis is based on endomyocardial biopsy (EMB) or autopsy or by the coexistence of positive biomarkers (troponin >99th upper reference limit or elevated creatine kinase myocardial band [CK–MB]) and cardiac MRI findings consistent with AM according to the 2018 updated Lake Louise Criteria. Results 77 patients (median age 25 years [IQR 20–35], 15% female) were included and followed–up for 147 days [IQR 74–215]. Follow–up CMR was available in n=49 patients and showed no changes in biventricular ejection fraction (EF) as compared to CMR at diagnosis (left ventricular EF: 59%[55–65]vs. 60%[57–64], p=0.507, right ventricular EF: 56%[52–62]vs. 57%[52–61], p=0.563, respectively). Late gadolinium enhancement was present in all patients at diagnosis and persisted in only n=39 (79.6%) at follow–up (p=0.001), generally sparing the anterior wall and the septum. N=10 (20.4%) had a persistent edema based on T2–weighted short tau inversion recovery (STIR) sequences, with predominant involvement of inferior or inferior–lateral walls. The proportion of patients with increased T1 and T2 mapping signals significantly decreased at follow–up (n=13 (68%) vs. n=4 (13%),p Conclusions At mid–term follow–up, patients who experienced an acute myocarditis after a mRNA COVID–19 vaccine had preserved biventricular EF. The rate and localization of residual scar or edema on CMR is in line with classic viral myocarditis with a good prognosis. This new piece of information should further reassure patients who experience acute myocarditis after mRNA COVID–19 vaccination.

Myocardial contusion (MC) is a note rare and potentially fatal complication of blunt chest trauma (BCT). The spectrum of manifestations of post–traumatic cardiac injury varies widely: from clinically silent injuries to severe reductions in cardiac function, myocardial hematomas, heart ruptures, and life–threatening arrhythmias1. There is no unique definition for this entity, and the diagnostic criteria proposed by different authors vary widely. Some authors define MC as a mild increase in cardiac biomarkers in the context of chest trauma, while for others the diagnosis requires evidence on imaging of pathologic findings2. Consequently, the true incidence of MC remains unknown, varying in reports between 8% and 71%3. We describe a case of cardiac contusion secondary to a low–energy trauma manifested as persistent ST elevation and pathologic elevation of myocardiocytosis markers, with consequent myocardial stunning of the right ventricular free wall. As there is no consensus regarding the correct diagnostic pathway, it is essential to integrate first–level pathologic examinations (ECG and laboratory diagnostics) with cardiac magnetic Resonance Imaging (MRI) to define the presence of cardiac contusion and its extent, especially if the echocardiographic data are unconclusive.

Objectives The aim of this study was to assess the natural history and clinical burden of moderate aortic stenosis and to investigate the interaction of left ventricular ejection fraction and of age with prognosis. Background The mortality risk of patients with moderate aortic stenosis is not well known but recent studies suggested that it might negatively affect prognosis. Methods A systematic research was conducted on PubMed. The inclusion criteria were: 1) inclusion of patients with moderate aortic stenosis; 2) report of the survival at 1–year follow–up (minimum). Incidence ratios related to all–cause mortality in patients and controls of each study were estimated and then pooled using a fixed effects model. Meta–regression analysis was performed to assess the impact of left ventricular ejection fraction and age on the prognosis of patients with moderate aortic stenosis. Results Fifteen studies and 11,596 patients with moderate aortic stenosis were included. All–cause mortality was significantly higher among patients with moderate aortic stenosis than among controls: 10.7% (95% CI: 0.1010–0.1136) vs 4.5% (95% CI: 0.0438–0.0454) at 1–year (p < 0.0001), 17.7% (95% CI: 0.1692–0.1854) vs 7.6% (95% CI: 0.0754–0.0775) at 2–year, 23.0% (95% CI: 0.2204–0.2387) vs 9.9% (95% CI: 0.0973–0.0997) at 3–year, 27.9% (95% CI: 0.2685–0.2899) vs 11.9% (95% CI: 0.1177–0.1203) at 4–year, and 32.4% (95% CI: 0.3125–0.3360) vs 14.2% (95% CI: 0.1402–0.1430) at 5–year follow–up. Left ventricular ejection fraction did not significantly impact on the prognosis of patients with moderate aortic stenosis (estimate = –0.0020; 95% CI: –0.0078–0.0038; p = 0.4584), unlike of age (estimate = 0.0067; 95% CI: 0.0007–0.0127; p = 0.0323). Conclusions Moderate aortic stenosis is not a benign disease. Further studies are necessary to confirm the prognostic impact of this valvulopathy and the possible benefit of the aortic valve replacement. Figure 1: All–cause mortality of patients with moderate aortic stenosis (red) vs controls (black) at 1–, 2–, 3–, 4– and 5–year follow–up. Figure 2: Impact of left ventricular ejection fraction on prognosis of patients with moderate aortic stenosis. Figure 3: Impact of age on prognosis of patients with moderate aortic stenosis.

Background The 2018 ESH guidelines have revised the therapeutic goals of cardiological Hypertensive Emergencies (HE) with an indication for a more intensive (target < 140/90 mmHg) and rapid (immediate) Blood Pressure (BP) reduction. Cardiac acute organ damage during HE includes acute myocardial infarction, pulmonary edema, unstable angina pectoris and aortic dissection. However, how much these indications have been applied in clinical practice to date it’s unknown. Aims The first purpose of our study is to analyze the prevalence and clinical characteristics of cardiological HE in our institution. The second purpose is to compare the year before the release of the 2018 guidelines (2017) with the subsequent years (2019) trying to verify adherence to guidelines. Methods This is a single–center retrospective study conducted at the Niguarda Hospital. All patients aged ≥ 18 years with Systolic BP≥ 180 mmHg and/or a Diastolic BP ≥ 120 mmHg with Cardiological Emergency were enrolled. From the Emergency Department (ED) data clinical, anamnestic, blood pressure, symptoms, drug treatment and target achievement were registered. Results Patients with BP > 180/120 mmHg in 2017 were 706 out of a total of 73795 accesses (0.96%) and 601 over 67273 (0.89%) in 2019. 246 (34.84%) in 2017 were HE of which 144 (58.53%) were cardiological: aortic dissection 1 (0.69%), acute coronary syndrome 52 (36.11%), acute pulmonary edema 35 (24.30%), cardiac decompensation 91 (63.19%). During 2019 similar figures were founded with 286 (47.58%) HE of which 286 (47.58%) were cardiological: aortic dissection 2 (1.43%), acute coronary syndrome 43 (30.93%), acute pulmonary edema 20 (14.39%), cardiac decompensation 76 (54.68%). The reduction in BP obtained in ED was significantly greater in 2017 than in 2019 (44.7±31.4 vs 35.4±24.5 mmHg, p = 0.011) with a lower target reaching in 2019 (28.9 vs 51.4%, p Conclusions The recommendation for a more intense and rapid BP reduction in cardiological HE seems to be not accepted from ED clinicians that persist to reduce BP accordingly to previous guidelines.

A 39–year–old Filipino man was admitted for dyspnea and lower limb edema for about a month, in combination with stable cardiac enzymes movement (TnT 128>78>115 ng/dl), fluctuating unspecific inflammatory profile and hepatic impairment. Trans–thoracic echocardiography confirmed heart failure (HF) in a setting of eccentric left ventricular hypertrophy, diffuse hypokinesia and severe global functionreduction. Despite the absence of typical chest pain, the presence of cardiovascular (CV) risk factors (DMT2, smoking, dyslipidemia), previous alcoholism and the finding of widespread ventricular repolarization ECG changes seemed to suggest an ischemic or multifactorialorigin of the HF. After the finding of a critical trivascular coronary artery disease on coronarography and a pulmonary nodule on chest CT, the cardiac magnetic resonance (CMR) confirmed the diagnosis of severe dilated HF with evidence of a diffuse wall signal hyperintensity in STIR sequences and a intramyocardial and subepicardial patchy LGE pattern of non–ischemic meaning. The possible ischemic etiology was thus overlaid with an inflammatory disease, leading to assume sarcoidosis or myocarditis be the cause of HF. The main screening tests (ACE and immunologic–infectious profile) were negative a a PET/CT scan confirmed a diffuse cardiac inflammation with no focal hypercaptant lesions. Therefore, sarcoidosis was ruled out, and an endomyocardial biopsy (BEM) was performed, and resulted, however, inconclusive. Following, an unexpected finding revealed through a more scrupulous anamnesis: a long–time abuse of a methamphetamine (MDMA) prevalent in the Filipino community called Shaboo. This type of MDMA is accompanied by multiple CV system impacts, including MDMA–associated cardiomyopathy (MACM), a clinical picture compatible with the findings obtained by CMR and BEM performed. After discussion in Heart Team and therapeutic optimization, the patient was candidate for coronary artery bypass. Thus, with the correct diagnostic definition and treatment of HF triggers, an improvement in clinical and left ventricularfunction was marked (EF 45%). Monitoring will allow evaluation of the evolution of the changes found at CMR and will document eventually reversibility of MACM after protracted abstention from MDMA abuse.

Background The use of a novel extracellular oxygen carrier (EOC) preservation additive known as HEMO2Life has recently been shown to lead to a superior preservation of different types of solid organs. Our study aimed to investigate the effect of this EOC on extending lung preservation time and its mechanism of action. Methods Donor pigs were randomly allocated to either of the following 2 groups (n = 6 per group): (1) 36 hours cold preservation or (2) 36 hours cold preservation with 1 g/liter of EOC. The lungs were evaluated through 12 hours of normothermic ex vivo lung perfusion (EVLP) followed by a left-single lung transplant into a recipient pig. Grafts were reperfused for 4 hours, followed by right pulmonary artery clamping to assess graft oxygenation function. Results During EVLP assessment, EOC-treated lungs showed improvements in physiologic parameters, whereas the control lungs deteriorated. After a total of 48 hours of preservation (36 hours cold + 12 hours normothermic EVLP), transplanted grafts in the treatment group displayed significantly better oxygenation than in the controls (PaO2/FiO2: 437 ± 36 mm Hg vs 343 ± 27 mm Hg, p = 0.041). In addition, the use of EOC led to significantly less edema formation (wet-to-dry ratio: 4.95 ± 0.29 vs 6.05 ± 0.33, p = 0.026), less apoptotic cell death (p = 0.041), improved tight junction preservation (p = 0.002), and lower levels of circulating IL-6 within recipient plasma (p = 0.004) compared with non-use of EOC in the control group after transplantation. Conclusion The use of an EOC during an extended pulmonary preservation period led to significantly superior early post-transplant lung function.

Summary Background A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation. Methods We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044. Findings From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV-positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16·76–24·75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20–12 000] vs 4390 IU/mL [1170–112 000] at day 7; p=0·048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV-positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV-negative donors. The most common grade 3–4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment. Interpretation Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor–recipient transmission. Funding Canadian Institutes of Health Research.

Cold static preservation on ice (~4°C) remains the clinical standard of donor organ preservation. However, mitochondrial injury develops during prolonged storage, which limits the extent of time that organs can maintain viability. We explored the feasibility of prolonged donor lung storage at 10°C using a large animal model and investigated mechanisms related to mitochondrial protection. Functional assessments performed during ex vivo lung perfusion demonstrated that porcine lungs stored for 36 hours at 10°C had lower airway pressures, higher lung compliances, and better oxygenation capabilities, indicative of better pulmonary physiology, as compared to lungs stored conventionally at 4°C. Mitochondrial protective metabolites including itaconate, glutamine, and

EDIT16 CNCE 1140, *4, a-d6,e4, A-C6, D8, E6, F8, G6, H4, Handschriftliches Exlibris: "Biblioth. Archid. Ferdinandi" 990020167720205503_0001 Exemplar der ETH-BIB, Handschriftliches Exlibris: "Bibliothecae Archid. Ferdinandi" 990020167720205503_0002 Exemplar der ETH-BIB

Background Transmission of latent human cytomegalovirus (HCMV) via organ transplantation with post-transplant viral reactivation is extremely prevalent and results in substantial adverse impact on outcomes. Therapies targeting the latent reservoir within the allograft to mitigate viral transmission would represent a major advance. Here, we delivered an immunotoxin (F49A-FTP) that targets and kills latent HCMV aiming at reducing the HCMV reservoir from donor lungs using ex-vivo lung perfusion (EVLP). Methods HCMV seropositive human lungs were placed on EVLP alone or EVLP+1mg/L of F49A-FTP for 6 hours (n=6 , each). CD14+ monocytes isolated from biopsies pre and post EVLP underwent HCMV reactivation assay designed to evaluate viral reactivation capacity. Off-target effects of F49A-FTP were studied evaluating cell death markers of CD34+ and CD14+ cells using flow cytometry. Lung function on EVLP and inflammatory cytokine production were evaluated as safety endpoints. Results We demonstrate that lungs treated ex-vivo with F49A-FTP had a significant reduction in HCMV reactivation compared to controls, suggesting successful targeting of latent virus (76% median reduction in F49A-FTP vs. 15% increase in controls, p=0.0087). Furthermore, there was comparable cell death rates of the targeted cells between both groups, suggesting no off-target effects. Ex-vivo lung function was stable over 6 hours and no differences in key inflammatory cytokines were observed demonstrating safety of this novel treatment. Conclusions Ex-vivo F49A-FTP treatment of human lungs targets and kills latent HCMV, markedly attenuating HCMV reactivation. This approach demonstrates the first experiments targeting latent HCMV in a donor organ with promising results towards clinical translation.

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life-sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.

Availability of organs is a limiting factor for lung transplantation, leading to substantial mortality rates on the wait list. Use of organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), would increase organ donation, but these organs are generally not offered for transplantation due to a high risk of transmission. Here, we develop a method for treatment of HCV-infected human donor lungs that prevents HCV transmission. Physical viral clearance in combination with germicidal light-based therapies during normothermic ex-vivo Lung Perfusion (EVLP), a method for assessment and treatment of injured donor lungs, inactivates HCV virus in a short period of time. Such treatment is shown to be safe using a large animal EVLP-to-lung transplantation model. This strategy of treating viral infection in a donor organ during preservation could significantly increase the availability of organs for transplantation and encourages further clinical development., Organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), are not offered for transplantation due to a high risk of transmission. Here, Galasso et al. develop a method for treatment of HCV-infected human donor lungs that is safe and prevents HCV transmission in the pig model.

The Belle II experiment will operate at the SuperKEKB e+ e− collider, designed to reach a top luminosity of $8 \times 10^{35}$ at the $\Upsilon $ (4s) resonance. The high background environment of the accelerator poses serious challenges to the design of the detector. In particular, the Belle II collaboration is developing an ambitious upgrade program that involves the forward electromagnetic calorimeter. We will use pure CsI crystals, since they have less scintillation time but unfortunately much lower light yield. The electromagnetic calorimeter upgrade is subject to the same detector constraints as the first design; an intense research and development program on photon-detectors and front-end electronics has been initiated by the Italian collaboration. Our preliminary results show that a readout chain using avalanche photodiodes (APDs) to match the detector constraints and a dedicated front-end card for the readout meet the Belle II collaboration requirements. In this paper, we will show the experimental setup and detail the main characteristics of the read-out and power distribution system since the front-end card hosts both a low noise preamplifier and a power regulator to set the single APD bias voltage. The main HV module has been developed for this purpose to deliver a low noise power distribution to the front-end cards. All the relevant parameters of the front-end system can be set and monitored via Ethernet using the Experimental Physics and Industrial Control System. Slow control and monitoring functions in Belle II are performed by a dedicated hardware. The platform has been designed as an uP-based service-oriented platform, capable to offer an integrated solution for all the needs of data acquisition, analysis, and network functions.

Purpose The majority of potential donor lungs are not being used. The primary reason for underutilization is the concern for primary graft dysfunction (PGD). There is currently no clinically available therapy for PGD. Alpha 1 antitrypsin (A1AT) is a serine protease inhibitor with anti-inflammatory and cytoprotective properties. We and others have shown benefits of A1AT in small and large animal lung transplant studies. Before performing clinical trials, evidence of therapeutic efficacy in human lungs would be valuable. We tested the effect of A1AT given during ex vivo lung perfusion (EVLP) to human lungs rejected for transplantation. Methods Double lung blocks rejected for transplantation (n=8) were divided and placed on separate EVLP circuits for 12h. Lungs were randomly assigned to receive A1AT or placebo, with the contralateral lung serving as control for the treated lung. Outcome measures included: hourly physiologic lung function, perfusate loss, wet-dry weight ratio, inflammatory mediators, endothelin-1 (ET-1), and zonula occludens tight junction protein‐1 (ZO‐1, immunofluorescence staining). Results The A1AT-treated group demonstrated significantly better lung function: higher pO2 and compliance (Fig A), lower pulmonary artery pressure (-0.4 mmHg p= 0.04) and vascular resistance (-30.4 dynes·s cm−5 p= 0.01). Perfusate loss, a surrogate for lung permeability, was lower in the A1AT group, as was the wet-dry ratio (Fig B). A1AT also decreased ET-1 levels in perfusate (Fig C) and increased ZO-1 expression on endothelial cells (Fig D). Conclusion In this study we demonstrated that human A1AT was able to improve the quality of severly injuried human lungs, likely through endothelial cell protection. The encouraging results justify a clinical trial, in order to improve donor lung quality and clinical outcomes in lung transplantation. Our study also illustrates that testing selected drugs on injured human lungs on EVLP is a viable strategy prior to clinical application.

Purpose Post-transplant CMV reactivation from latently-infected lung allografts is extremely prevalent and results in inferior long-term outcomes. CMV latently infected cells ubiquitously express a viral surface protein, US28. We aimed to evaluate the therapeutic effects of a novel immunotoxin (F49A-FTP) that targets US28 in human lungs during EVLP, with the ultimate goal of minimizing or preventing CMV transmission and reactivation post-transplantation. Methods Human lungs rejected for transplantation were randomly placed on EVLP alone or EVLP+1mg/L of F49A-FTP (n=6 each) for 6 hours. Biopsies were collected pre and post EVLP and subjected to an in vitro assay designed to evaluate viral reactivation capacity (Fig 1A). Based on US28’s homology to the human CX3CR1 chemokine receptor, potential off-target effects of the toxin were studied evaluating cell death markers of CD34+ and CD14+ using flow cytometry, and the ratio of cells post:pre perfusion were calculated. Lung function on EVLP and inflammatory cytokine production were evaluated as safety endpoints. Results Delivery of F49A-FTP during EVLP showed no acute toxic events demonstrated by no significant differences in lung physiology and levels of IL-8, IL1-b and IFN-γ between the groups. Furthermore, while control lung tissue demonstrated a median increase from baseline of 32% (Range -16% to +112.5%) in viral reactivation, treated lungs demonstrated a significant median reduction in CMV reactivation of 76% (Range -15% to -99.9%) (Fig 1B, p=0.0087). No off-target effects were noted upon F49A-FTP delivery, demonstrated by similar amounts of cell death between the groups (Fig 1C). Conclusion We demonstrate that ex vivo F49A-FTP treatment of human lungs on EVLP markedly attenuates CMV reactivation and could potentially be used to treat donor organs prior to transplant. Ongoing in vivo reactivation experiments using the EVLP treated samples in a humanized mouse will further validate these findings.

During last years, the evolution of process supervision shifted from a rule-base-oriented to a knowledge-base-oriented approach, where the automation systems relieve the human operator from most tedious and repetitive low-level information manipulation tasks; knowledge is considered more important than man by the introduction of applications for strict process control and tools for decision. In this context, Danieli Automation set itself a goal to design a new generation of supervision and control systems, which could provide added value to the operation of plant areas, taking advantage of recent advancements in user interface and information technology. These goals were met by creating new applications in which the know-how is transferred from operators to automation systems and the humanmachine interfaces are optimized in order to improve the quality of the operator work, making decisions faster and more accurate. The result is an innovative man-machine interface, called OPERATOR ASSISTANT. This paper aims to explain all the studies that have been done to develop this new tool, from ergonomics to the choice of the development platform, passing through the decision for the multitouch technology, the minimization of complexity, the consideration of cultural factors and the restraint of the emotional stress for the user. Furthermore it outlines the activities that are currently being made to optimize the product.

Purpose Microbial infection in donor lungs decreases organ utilization in transplantation. Previous studies have demonstrated high-dose gaseous Nitric Oxide (gNO) to be effective against bacteria, however, this concept has not been studied in the context of lung transplantation. The present study explores the antimicrobial effects and the safety of continuously inhaled high-dose gNO. Methods Effects of gNO on strains of P. aeruginosa, S. aureus, E. coli and Burkholderia cepacia (purchased from American Type Culture Collection) were performed in vitro. Agar plates were inoculated and transferred into either control (medical air) or treatment chamber (medical air + 200 ppm gNO) for 6 h. Safety of continuously inhaled high-dose gNO were studied in a porcine normothermic ex vivo lung perfusion (EVLP) model. Donor lungs with minimal cold ischemia (2h) were randomized (n=4 each) into control (normal ventilation setting) and treatment (normal ventilation setting + high-dose of gNO) group. Physiologic and biologic measures were monitored over 12 h of EVLP. Results gNO significantly reduced all strains of bacteria when compared to control (n=3 per group, Fig.1A): P. aeruginosa (5.8 ±1.27 vs 9.2 ±0.40 Log10CFU/mL, p= 0.01), S. aureus (5.6 ±0.65 vs 9.1 ±0.66 Log10CFU/mL, p= 0.002), E. coli (5.3 ±1.20 vs 9.4 ±0.47 Log10CFU/mL, p= 0.005) and Burkholderia cepacia (7.0 ±0.51 vs 8.9 ±0.57 Log10CFU/mL, p= 0.01). No significant adverse effects in lung function during EVLP were observed in lungs receiving 12h of continuous high-dose of gNO (Fig. 1B). Inflammatory cytokines at 1, 6 and 12h were similar between control and treatment (Fig. 1C). NO2 levels were Conclusion Continuous high dose gNO at 200 ppm is effective towards reducing common respiratory pathogens in vitro. Inhaled high-dose gNO appears to be safe during 12h EVLP. We are further exploring this treatment using infected human lungs. If successful high dose gNO could be part of EVLP clinical protocols.

Purpose Donor to recipient CMV mismatch leads to high incidence of CMV infection post lung transplant leading to inferior long-term patient outcomes. CMV latently infected cells ubiquitously express a surface marker, US28. We aimed to evaluate the therapeutic effects of a novel fusion toxin protein (F49A-FTP) that targets US28 in human lungs during EVLP, with the ultimate goal of minimizing or preventing CMV reactivation post transplantation. Methods Human lungs rejected for transplantation were randomly placed on EVLP alone or EVLP+1mg/L of F49A-FTP (n=6 each) for 6 hours. Biopsies were collected to evaluate viral reactivation using an in vitro assay that induces latent CMV to reactivate to an infectious phase. Since US28 has 38% homology to the human CX3CR1 chemokine receptor, potential off-target effects of the toxin were studied using flow cytometry for cell death assessment of CD34+ and CD14+ cells. Lung function on EVLP was evaluated as a safety endpoint. Results F49A-FTP was delivered through the PA on EVLP with no acute toxic events based on physiological parameters (Figure 1A). We performed an in vitro assay using tissue samples obtained after EVLP to stimulate CMV to reactivate in order to assess efficacy of the drug. After primary culture from lung tissue samples, relative reactivation events (assessed with IFF staining for IE protein of lytic CMV, Figure 1B) occurred in 100% of controls vs. only 0.04±0.02% of treated lungs. For off-target analysis, we performed flow cytometry and calculated the ratio of post:pre perfusion CD34+ and CD14+ cells (Figure 1C). There were no changes in number of cells for both groups: CD34+ ratio 0.8±0.5 vs. 0.6±0.5 (control and F49A-FTP, respectively, p=0.4974); CD14+ ratio 1.54±0.74 vs. 1.66±1.13 (control and F49A-FTP, respectively, p=0.8660). Conclusion Our study demonstrates that ex vivo F49A-FTP treatment of human lungs on EVLP markedly attenuates CMV reactivation. Ongoing ex vivo and in vivo reactivation experiments will confirm these findings.

Purpose In pre-clinical studies we have demonstrated the ability of light-based therapies - UVC and photodynamic therapy (PDT) during EVLP to inactivate HCV in donor lungs. In a step-wise application of this technology to clinical transplantation, we designed a clinical trial to evaluate to effects of UVC treatment using NAT+ HCV donor lungs followed by transplantation. Methods Twenty patients receiving NAT+ HCV lungs were included in the study. In the control group, lungs were subjected to 5-6h of EVLP whereas in UVC group, lungs were subjected perfusate irradiation with UVC (254 nm, 31mW/cm²) followed by transplantation. Results 11 patients received lungs subjected to EVLP alone, and 9 patients received lungs subjected to EVLP+UVC. Donor viral loads were similar between the 2 groups (3585000 IU/ml vs. 3480000 IU/mL, p=0.56). During EVLP, lung function was stable and similar between the 2 groups. 19/20 patients developed viremia. Perfusate and tissue levels of HCV by PCR during EVLP were not significantly affected by UVC treatment (Fig.1A), however, the UVC group showed a marked delay in developing viremia post-transplantation (Fig 1B). Median day 7 viral loads were 4390 vs. 168 IU/ml; p=0.27 in control vs. UVC group respectively. The proportion of patients with viral loads less than 3-log copies at day 7 was 2/11 (18%) in control vs. 5/8 (62.5%) in UVC group; p=0.07. Survival post lung transplantation is 100% in both groups with a mean follow up of 162 (14-385) days. Conclusion This is the first clinical trial evaluating a therapeutic intervention during EVLP. As in our pre-clinical studies, UVC does not alter virus quantities measured by PCR (virus fragments) during EVLP, however it does appear to confer impairment in virus infectivity. The combination of UVC therapy with an ultra-short course of direct anti-virus agents may provide the ability to prevent transmission altogether, allowing expansion of transplantation using HCV+ organs.

Purpose Extracorporeal membrane oxygenation, veno-venous configuration (VV-ECMO) is an effective intervention to improve gas exchange in patients with severe respiratory failure, refractory to conventional treatments, or as a bridge to lung transplantation. However, optimal mechanical ventilation (MV) strategies during VV-ECMO to minimize ventilator-induced lung injury are undetermined. While there is general consensus in minimizing tidal ventilation, the potential benefit of high positive end-expiratory pressure (PEEP) strategies in optimizing cardiopulmonary interaction and reducing the severity of lung injury remains unclear.We hypothesize that PEEP-induced alveolar recruitment will reduce lung injury during VV-ECMO for ARDS, in comparison to atelectatic lungs. Methods Yorkshire pigs weresedated, paralyzed, mechanically ventilated,and cannulated for VV-ECMO support. Lung injury was done by two serial bronchoscopic instillations of gastric juice to achieve a P/F ratio Results During VV-ECMO, gas exchange and hemodynamic parameters remained stable and comparable in the two groups, despite the very low tidal volume delivered (HP 54 ml ±; LP 41 ml ±11). Lung volume was higher in the HP compared with the LP group, and remained unchanged during the 5 hours of VV-ECMO support. At the end of the 5 hours of ECMO support, in the dependent lung areas the W/D was significantly higher in the HP compared to LP group (HP 11.1, 95% CI: 10.5-11.7; LP 9.2, 95% CI: 8.2-10.3); in the non-dependent areas the W/D was significantly higher in the LP compared to HP group (LP 6.3, 95% CI: 5.6-6.9; HP 5.3, 95% CI: 4.9-5.8). Conclusion VV-ECMO for severe acute respiratory failure MV with very low tidal volume and LP reduces regional lung edema in the dependent areas, while HP reduces edema.More studies are required to characterize the mechanisms of these findings.

Purpose Uncontrolled donation after death by circulatory criteria (uDCD) has the potential to alleviate some of the shortage of suitable lungs for transplantation. Non-Perfused Organ Donors (NPOD) differs from uDCD donors in that only lungs are obtained as no reperfusion is instituted after individuals suffer an unexpected sudden cardiac arrest. Family are approached rapidly by trained coordinators for consent to donate lungs. This study reviews our initial experience and challenges with NPOD donation. Methods Data were collected from donors and recipients involved in NPOD lung transplants between February 2016 and October 2018. We describe NPOD donor volumes, ischemia time, utilization rates, length of intensive care unit (ICU) and hospital stay, and survival. Results There were 101 referrals during this period. Of the 34 approached for donation, consent was obtained in 24 cases, and the lung transplant team evaluated 24 NPOD donors on site. Eleven donors were declined before retrieval because of medically unsuitable lungs, and 4 donors were declined after retrieval due to severe lung injury on site. Nine lungs underwent ex vivo lung perfusion in order to evaluate suitability for transplantation and eventually 3 were used for transplantation. Thus, the total utilization rate from consented donors was 12.5%. The mean warm ischemic time was 160 minutes (range: 106-175 minutes). The mean age of 3 recipients was 48 ± 2.5 years. The 30-day mortality was 0%. One patient bridged to transplantation on extracorporeal membrane oxygenation (ECMO) was kept on ECMO for 5 days after transplant. Median ICU stay was 20 days (range: 5-78 days). Median hospital stay was 47 days (range: 18-100 days). Two out of 3 patients are alive at a median of 716 days (range: 100-936 days) with good performance status and lung function. One patient that was on ECMO prior to transplantation died of multisystem organ failure 100 days after transplantation. Conclusion This study demonstrated the potential for NPOD lung donation. However, utilization rates are low. Therefore, improved strategies of lung preservation before retrieval are required to increase and select lungs that are utilizable for transplantation.

Purpose Ex vivo lung perfusion (EVLP) has become an invaluable tool in clinical lung transplantation (LTx). EVLP has enabled the assessment and rescue of donor organs that would have otherwise been discarded for LTx; however, determining which marginal organs are suitable for transplant remains challenging and relies largely on clinical assessment expertise. To this end, we describe our efforts to develop and validate a perfusate-based diagnostic test that will assist transplant teams in the EVLP decision-making process. Methods From 2008 to 2017, approximately 300 clinical EVLP cases were performed. A retrospective study was conducted using biobanked perfusate samples to develop and validate a set of biological mediators that predict: (i) whether a lung would be acceptable for transplant following EVLP; and (ii) the contribution of that donor lung to a favorable recipient outcome. A prospective study of an additional 50 EVLP cases is currently underway to further validate the EVLP predictive test. Results Using simple regression, a model that included donor characteristics and perfusate-derived mediators of inflammation (e.g., interleukin 6 and 8, and others) predicted whether or not a lung would be deemed acceptable for transplant with an overall accuracy of 70% [95% CI: 64-76%] (n=259). When the transplanted cases were further sub-stratified for recipient outcomes (e.g., ICU length of stay), our score's predictive performance improved to 83% [95% CI: 76-90%] (n=139). Next, a visual representation of the model was created and used in real-time alongside our clinical EVLP cases. In the ongoing test set of approximately 25 EVLP cases, the model accuracy is maintained at 71%. Conclusion We have developed and validated an EVLP test in the largest known cohort of EVLP cases to date. This score is able to predict whether a marginal donor lung will be acceptable for transplant following EVLP assessment. Furthermore, we can determine thresholds, independent of any recipient factors, that are associated with excellent transplant outcomes. This test represents a major step forward in the utilization of EVLP in lung transplantation by providing a useful metric that will better assist transplant teams to select lungs for successful outcomes on EVLP and subsequent transplantation.

Purpose One of the most promising strategies to increase organ donation is the use of organs from donors with Hepatitis C (HCV). We evaluated the safety of transplanting NAT+HCV donors into non-infected lung recipients. Methods Between Oct 2017 and Oct 2018, NAT+HCV donors in North America were considered. Recipients consented to receive such organs under study protocol NCT03112044. Exclusion criteria included existence of liver disease or multi-organ transplant. Outcomes of study recipients were compared to patients receiving non-infected donors. Primary endpoints were survival and HCV status at 6 months after transplantation. All patients becoming viremic received S/V starting at least 2 weeks after transplantation. Results During the one-year study period 200 lung transplant procedures were performed at our center. Of these, 20 (10%) were from NAT+ HCV donors. Compared to standard donors, HCV donors were significantly younger (33y vs. 52y, p=0.002), more likely to be located in the United States vs. Canada (75% vs 5%, p=0.001), and more likely to be smokers (95% vs. 47%, p=0.0001). Donor P/F ratio (383 mmHg vs. 424 mmHg) and proportion of DCD (10% vs. 27%) were not statistically different between the 2 groups. Recipient age, lung disease, urgency status and positive donor HLA crossmatch were similar between the 2 groups. There was a significantly higher proportion of single lung transplants in the HCV group (55% vs. 15%, p=0.002). Post-transplant time on ventilation, ICU and hospital length of stay, use of ECMO and survival (100% in HCV group) were similar between the 2 groups. All patients, except 1 became viremic within 1 week after transplantation. 12 weeks treatment with S/V started at a median of 21 days after transplantation (range 14-71). All patients achieved negative HCV PCR from 2 to 6 weeks after treatment initiation. Two patients presented with HCV relapse within 3 months after S/V termination. One of the relapses was associated with alteration in liver enzymes. Conclusion Excellent intermediate-term clinical outcomes were achieved using NAT+HCV donors to non-infected recipients and this practice should continue to be encouraged. However, a higher relapse rate (10% to date) than previously reported in non-lung transplant patients was observed and novel strategies aiming at prevention of transmission should be further studied.

Background: The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. Methods: A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. Results: Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. Conclusion: Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention.

Objective To report the first case of prophylactic laser treatment to prevent blindness in a patient who was diagnosed with Norrie's disease by genetic testing with amniocentesis. Design Case report. Participants A 2-year-old white boy with Norrie's disease. Methods A 37-week gestational age male with a family history of Norrie's disease was born via Cesarean section after the mother had undergone prenatal amniocentesis fetal-genetic testing at 23 weeks of gestation. A C520T (nonsense) mutation was found in the Norrie's disease gene. After examination under anesthesia confirmed the diagnosis on the first day of life, laser photocoagulation was applied to the avascular retina bilaterally. The patient was followed closely by ophthalmology, pediatrics, and occupational therapy departments. Main Outcome Measures Functional outcome, as documented by Teller visual acuity and formal occupational therapy testing, and anatomic outcome, as documented by Retcam photography and fluorescein angiography. Results Complete regression of extraretinal fibrovascular proliferation was observed 1 month after laser treatment. No retinal detachment had occurred to date at 24 months. Teller visual acuity at 23 months of life was 20/100 in both eyes. The patient's vision and developmental milestones were age appropriate. Conclusions Pre-term genetic diagnosis with immediate laser treatment after birth may preserve vision in individuals affected with Norrie's disease. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To report 6-month and 1 year outcomes of eyes treated for neovascular glaucoma (NVG) with intravitreal bevacizumab injection and panretinal laser (PRP) compared to those receiving PRP alone.retrospective, consecutive case series.Charts of patients with NVG from retinal ischemia and at least 6 months of follow-up were reviewed. Patients were treated with one injection of 1.25 mg intravitreal bevacizumab followed by PRP or with PRP alone. The primary outcome was the long-term angle anatomy. Secondary measures included intraocular pressure (IOP), visual acuity, patient compliance, and control of systemic diseases.Fourteen eyes of 12 patients treated with bevacizumab and PRP and 15 eyes of 11 patients treated with PRP alone were included in the study. Mean sectors of open angle at baseline was 1.31 in the bevacizumab group and 1.47 in the retinal ablation group (P = 0.73). Mean sectors of open angle was 2.14 and 1.18 in the bevacizumab and retinal ablation groups, respectively (P0.05) at 6-month follow-up, and 2.27 and 1.18, respectively (P0.05) at 1-year follow-up. Mean baseline IOP was 32.3 mmHg (+/-14.8) in the bevacizumab group and 31.8 mmHg (+/-13) in the PRP group (P = 0.75). At 6-month follow-up, the mean IOP was 18.28 mmHg (+/-10) in the bevacizumab group and 23.33 mmHg (+/-14.6) in the PRP group (P = 0.05), and 19.12 mmHg (+/-6.8) and 26.2 mmHg (+/-18) (P = 0.1), respectively at 1-year follow-up. Nineteen patients were judged to be noncompliant, 10 had uncontrolled diabetes and 7 had uncontrolled hypertension.This study documents better long-term preservation of open angle and IOP control in eyes receiving bevacizumab along with PRP. We stress that NVG is still associated with poor visual acuity outcomes.

To determine the safety and efficacy of the Focus NIGHTDAY (CIBA Vision, Duluth, GA) silicone hydrogel contact lens in the management of refractory, moderate to severe dry eye signs and symptoms secondary to graft-versus-host disease (GVHD).Seven patients with GVHD and moderate to severe dry eye disease as determined by the Ocular Surface Disease Index (OSDI) questionnaire were fitted with a near plano Focus NIGHTDAY soft contact lens (SCL) used on a 7-night continuous-wear basis. Visual acuity, objective measures of dry eye disease (i.e., Schirmer I, tear breakup time, and corneal fluorescein staining), and OSDI scores were compared before SCL wear and after 1 week and 1 month of SCL wear.There was significant improvement in subjective assessment of dry eye symptoms (initial vs. 1-month OSDI score, 76.8 +/- 13.6 vs. 31.2 +/- 17.8, P0.0005, paired t test). In addition, patients had significant improvement in best-corrected visual acuity after 1 month of SCL wear (initial vs. 1-month logMAR visual acuity for the right eye, 0.23 +/- 0.050 vs. 0.04 +/- 0.027, P0.007; initial vs. 1-month logMAR visual acuity for the left eye, 0.22 +/- 0.049 vs. 0.04 +/- 0.020, P0.007, analysis of variance, Dunnett post hoc). There were no significant changes in results of Schirmer I testing, corneal fluorescein staining, or tear breakup time. No adverse events or complications of SCL wear were observed.The Focus NIGHTDAY contact lens can improve subjective dry eye symptoms and visual acuity in patients with refractory dry eye disease secondary to GVHD.

The aim of this study is to compare the weight loss of obese adolescents on two different low-calorie diets: fixed diet plan and calorie-counting diet. This is a randomized clinical study with 66 obese adolescents (body mass index Z score (ZBMI)>+3, 13.7±0.7 years, 60.6% male) with anthropometric, food intake, physical activity, laboratory, body composition and stage of pubertal development data evaluated. There was a reduction in the ZBMI in both groups (P