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Sudden death is one of the leading causes of death in adults with sickle cell anemia (SCA) but its etiology remains most often unknown. Ventricular arrhythmia (VA) carries an increased risk of sudden death but its prevalence and determinants in SCA is poorly studied. The aim of this study is to identify the prevalence and predictors of VA in SCA patients. From January 2019 to March 2022, 100 SCA patients were referred to ambulatory cardiology department to specifically analyze cardiac function and were prospectively included in DREPACOEUR registry. They underwent a 24-hour ECG monitoring (24h-holter), a transthoracic echocardiography (TTE) and laboratory tests on the same day. The primary end-point was the occurrence of VA, defined as sustained or non-sustained ventricular tachycardia (VT), more than 500 premature ventricular contractions (PVCs) on 24h-holter, or recent history of VT ablation. Mean age was 46±13 years, 48% of patients were male. VA was observed in 22 (22%) patients (9 non-sustained VT [range 4-121 consecutive PVCs]), 15 with more than 500 PVCs and 1 history of VT ablation). Male sex (81 vs. 34%, p=0.02), impaired global longitudinal strain (GLS: -16±1.9% vs. -18.3±2.7%, p=0.02), and decreased platelet count (226±96G/L vs. 316±130G/L, p=0.02) were independently associated with VA occurrence. GLS correlated to PVC load/24h (r=0.39, p

Several complications observed in sickle cell disease (SCD) are influenced by variation in hematological traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified 1000s of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested if these PTS associate with HT in SCD patients and can improve the prediction of SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD African-ancestry individuals. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these routinely measured HT were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (17.1-26.4%), associated with acute chest syndrome and stroke risk, and improved the prediction of vaso-occlusive crises. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 36% (P = 0.0008). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.

Aims This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (n=123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n=102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to Cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n=154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n=33) included the majority of pre-capillary PH whilst Cluster 2 (n=34) included post-capillary PH. No PH was found in Cluster 3 (n=27). After a follow-up of 11.4±2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate vs. 12% in Cluster 1 and 5% in Cluster 3 (P log-rank=0,003). Conclusion Cluster analysis of echocardiography variables identified 3 hemodynamic and clinical phenotypes amongst SCD patients, each predicting a different prognosis. This article is protected by copyright. All rights reserved.

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI &gt, 100), atovaquone, an anti-malarial (TI &gt, 34), and ciclesonide, an inhalable corticosteroid (TI &gt, 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.

Sickle cell disease (SCD) induces a chronic prothrombotic state. Central venous access devices (CVADs) are commonly used for chronic transfusions and iron chelation in this population. CVADs are an additional venous thromboembolism (VTE) risk factor. The role of thromboprophylaxis in this setting is uncertain. The objectives are: (1) to determine whether thromboprophylaxis reduces VTE risk in SCD patients with CVAD and (2) to explore characteristics associated with VTE risk. We identified adults with SCD and CVAD intended for chronic use (≥3 months) at two comprehensive SCD centers. Thromboprophylaxis presence; type; intensity; and patient-, catheter-, and treatment-related VTE risk factors were recorded. Among 949 patients, 49 had a CVAD (25 without and 24 with VTE prophylaxis). Thromboprophylaxis type and intensity varied widely. Patients without thromboprophylaxis had higher VTE rates (rate ratio (RR) = 4.0 (95% confidence interval: 1.2–12.6), p = 0.02). Hydroxyurea was associated with lower VTE rates (RR = 20.5 (6.4–65.3), p < 0.001). PICC lines and Vortex and Xcela Power implantable devices were associated with higher rates compared with Port-a-Cath (RR = 5.8 (1.3–25.9), p = 0.02, and RR = 58.2 (15.0–225.0), p < 0.001, respectively). Thromboprophylaxis, hydroxyurea, and CVAD subtype were independently associated with VTE. The potentially protective role of thromboprophylaxis and hydroxyurea for VTE prevention in patients with SCD and CVAD merits further exploration.

INTRODUCTION Vaso-occlusive crisis (VOC), hallmark of sickle-cell disease (SCD), is the first cause of patients' emergency room (ER) admissions and hospitalizations. Acute chest syndrome (ACS) is a life-threatening complication that can occur during VOC and prolong hospitalization and is one of the main causes of death in SCD patients. The PRESEV score, established by team members and colleagues, assesses the risk of developing ACS (Bartolucci et al., 2016). In addition, the score has been validated by an international multicenter study, involving 13 centers, distributed in five different countries (PRESEV 2 - ASH 2020). Throughout the first wave of the Covid-19 pandemic, VOC management for SCD patients was a major concern. Our sickle cell referral center set up a hotline to monitor patients suffering from VOC daily, and organized the deployment of home-care services when required. The success of this system during the first wave of the pandemic led to the establishment of DREPADOM, a home-care and hospitalization protocol for VOC management in patients who are at a low risk of developing ACS, as standard care. DESCRIPTION OF SETTING Patients eligible for DREPADOM are patients that arrive at the ER for a VOC with a low PRESEV score, meaning low risk of developing ACS; or patients that are discharged early following hospitalization for VOC. After physical examination and calculation of the PRESEV score, DREPADOM home hospitalization is systematically offered to patients arriving to the ER with a PRESEV score ≤ 5. If the patient agrees, the DREPADOM nurse coordinator then acts as a link between the pharmacist, the oxygen supplier, the homecare provider, and the DREPADOM medical platform to activate the home hospitalization protocol. This entails the delivery of oxygen supply at the patient's house, dispatch of a medical prescription of opioids and parenteral treatments, twice/thrice-daily visits from homecare nurses, and an on-call SCD expert. DREPADOM relies on a system of daily telephone calls with three levels of expertise and warning and a decision-making algorithm. This is supervised by SCD experts, who arbitrate according to the evolution of the situation (stopping the follow-up, continuing the follow-up as an outpatient, hospitalization) (Fig.1). Furthermore, nurses enter patient vitals in real-time during their daily visits on a dedicated online platform (Link4Life) that contains an integrated automatic alert system. Additionally, a daily phone update between the DREPADOM coordination and the homecare provider's coordination concerning status and evolution of the patient's global condition takes place. RESULTS Over a 6-month period, 39 patients were included in the DREPADOM home hospitalization protocol, 3 of which were included multiple times for a total of 42 inclusions. Mean age was 40 years old [±9], sex ratio was 14/25 (male/female), ER vs early discharge ratio was 21/22, and mean homecare follow-up was 3 days (±1) for both, patients arriving from the ER and early discharge patients. Throughout the third wave of the pandemic, when hospital saturation was a major concern, patients with PRESEV scores 5 ≤ 11 were also offered DREPADOM. Three patients were hospitalized (7%): one for an ACS, who was included during the 3 rd wave of the pandemic with a PRESEV score of 8; one for pyelonephritis unrelated to the VOC; and one for difficulties with venous access. No death was reported. PERSPECTIVES Preliminary satisfaction surveys show a great enthusiasm for DREPADOM, partly due to the high standard of care received, but also due to the shorter length of hospitalization. In fact, median hospital stay for VOC is 4 [3-7] days (Bartolucci, 2016) whereas median homecare follow-up was 3 [1-6] days. Figure 1 Figure 1. Disclosures Bartolucci: Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Emmaus: Consultancy; GBT: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Fabre Foundation: Research Funding.

Introduction: Sickle Cell Disease (SCD) is one of the most common genetic disease worldwide. The Acute Chest Syndrome (ACS) is a leading cause of death for SCD patients. The PRESEV1 study was set to produce a predictive score to assess the risk of an ACS development (Bartolucci et al., 2016). PRESEV2 was an international, multicenter prospective confirmatory study to validate the PRESEV score. This study aims at improving these predictions with the addition of a machine learning (ML) method. Patients and methods: Included patients follow PRESEV1 and PRESEV2 studies 'rules. The dataset thus contains 97 patients who developed an ACS episode (18.3%) against 434 patients who did not (81.7%). To compute the PRESEV score, we firstly used the method developed previously with the following variables as input: leukocytes, reticulocytes, hemoglobin levels and cervical spine pain. This method is based on a decision tree with fixed rules and is referred to as the decision tree method throughout this abstract. Secondly we used a ML method using a combined sampling method named SMOTEENN to balance the data and a C-Support Vector Classification (SVC) with fixed parameters to predict the score. This method produces a probability, with a threshold of 0.2, under which the patient is predicted to declare an ACS. We considered the dataset composed of PRESEV1 dataset and 80 percent of PRESEV2 with a randomly choice. The test dataset is thus composed of the remaining 20 percent of PRESEV2. This technique of random choice allowed us to use a 50-cross-validation and compute with Python an average score and a standard deviation (std). In order to allow comparison of the developed score with or without the addition of the ML method, rates were calculated by adding the weight of ACS representation in the dataset. Results: Among all parameters analyzed, the SVC method considered the following variables for calculation of the score: leukocytes, LDH, urea, reticulocytes and hemoglobin levels. A hundred and two adult patients with a severe VOC requiring hospitalization were included. Out of this pool of patients, 26 (25.5%) were predicted with a low risk of developing an ACS episode (SVC method). Sensibility and specificity were of 94.7% and 26.8%, respectfully. The negative predictive value (NPV) was of 95.8% and the positive predictive value (PPV) of 22.4%. Results are resumed in table 1. When compared to the PRESEV score (decision tree method), 44 patients out of 372 were identified with a low risk score (11.8%), Discussion and Conclusion: While the addition of a ML method did not allow the improvement of the sensibility or the NPV of the PRESEV score, it improved both the specificity and the PPV. The addition of artificial intelligence thus provides a better prediction with a higher percentage of "low-risk" patients. As highlighted in the international PRESEV study, this score could represent a useful tool for physicians in hospital settings, with limited beds. While the PRESEV score could allow a better management of "low risk" patients on one side, the identification of "high-risk" patients could also represent a serious advantage to physicians, as it could improve the feasibility of clinical trials for the prevention of this lethal complication in SCD patients. Disclosures Bartolucci: Innovhem: Other; Novartis: Research Funding; Roche: Consultancy; Bluebird: Consultancy; Emmaus: Consultancy; Bluebird: Research Funding; Addmedica: Research Funding; AGIOS: Consultancy; Fabre Foundation: Research Funding; Novartis: Consultancy; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; GBT: Consultancy.

INTRODUCTION Besides many problematics the Covid-19 pandemic has triggered, one issue remains the care of chronically ill patients. Regarding sickle cell disease (SCD), patients often present co-morbidities that could predispose them to poor outcome if they get infected. Vaso-occlusive crisis (VOC), a characteristic manifestation of SCD, is the first cause of patients 'hospitalizations. Here, we describe how our sickle cell referral center has managed outpatient care, with the constant preoccupation of minimizing risks for our patients and avoid them unnecessary trips to heavily burdened hospital settings. DESCRIPTION OF SETTING With the outbreak of Covid-19, our primary obsession was to provide continuous care for our patients, while ensuring their safety. All appointments were canceled when possible and patients were instructed to comply with the national lock down procedures. A hotline and helpdesk were setup as the first stage of our structure. When patients described symptoms of VOC and/or light breathing difficulties, they were enlisted for daily monitoring. This stage two consisted of calling patients daily with a specific set of questions, regarding management and improvement or deterioration of their symptoms. A dedicated team of dentists, who all volunteered and received specific training, managed both stage 1 and 2, along with nurses. SCD specialists supervised these two stages for medical decisions. All symptoms were recorded and reported. If symptoms disappeared, the patient's name was discarded from the list. If there was a worsening or no improvement of the patient's condition, he was moved to stage three by the SCD expert, with the deployment of homecare service. A whole network was then setup, with the delivery of oxygen supply at the patient's house, dispatch of a medical prescription to a neighboring pharmacy and daily visits from homecare service providers. Both opioids and parenteral treatments were prescribed and monitoring was performed daily (blood pressure, temperature, respiratory rate, pain, etc...). On the first visit, a blood sample was sent to a laboratory, to allow calculation of the PRESEV score (Bartolucci et al., 2016). This score, established by team members and colleagues, assesses the risk of acute chest syndrome (ACS). Moreover, it has just been validated by a multicenter international study (PRESEV II - under writing process). In case the PRESEV score was ≤ 5, home hospitalization was pursued. In case this score was ≥11, the patient was sent to hospital for constant monitoring and full comprehensive care. For low and intermediate scores, the patient was referred to hospital for any aggravation. The helpdesk was in constant interaction with nurses and providers of homecare services and status and evolution of the patient's global condition was reported daily for medical decisions. In addition, patients with home hospitalization care were called daily by the helpdesk, to ensure proper care and satisfaction. When home hospitalization was over, the patient automatically came back to stage two for a daily follow-up until full recovery. Early discharged patients could either re-integrate stage 2 or 3 for daily monitoring until full recovery. Out of the 305 patients included in this system, with a total of 2068 calls between March 23rd and May 29th. Seventy five were included for home hospitalization. Mean age was 36 years old [±9], sex ratio was 45/30 (female/male), mean homecare follow up was 6 days (±3), 16 patients also had Covid-19. Thirteen patients (17.3%) were hospitalized: one for an acute chest syndrome, two for a Covid-19 infection and nine for VOC management. Only one patient was in ICU due to a salmonella septicemia. No death was reported. PERSPECTIVES The Covid-19 pandemic has highlighted the need for profound reshaping of healthcare systems worldwide. In this particular context, the structure we have installed, DREPADOM, allowed follow up and monitoring of two profiles of patients: at-risk population of SCD patients and Covid-19 positive SCD patients. With the ongoing situation, our delocalized hospitalization system has proven interesting enough to enter a new phase: DREPADOM was selected as part of a public call for tenders, for financial support to make the structure permanent (DREPADOM - APRES). Disclosures Habibi: Pfizer: Consultancy; Bluebird: Consultancy; Addmedica: Consultancy; Novartis: Consultancy. Bartolucci:GBT: Consultancy; Roche: Consultancy; Emmaus: Consultancy; Innovhem: Other; Addmedica: Research Funding; HEMANEXT: Consultancy; Novartis: Consultancy; ADDMEDICA: Consultancy; Fabre Foundation: Research Funding; Novartis: Research Funding; Bluebird: Consultancy; AGIOS: Consultancy; Bluebird: Research Funding.

Highlights • Accessory proteins of coronaviruses play a role in virus adaptation to a new host. • Some FCoV harbour truncated gp3 proteins, an accessory protein peculiar of CCoV-I. • Deletions of gp3 do not influence their basic features. • Deletions impact the expression proteins levels in feline but not in canine cells. • All proteins localise in the ER despite the absence of a specific retention signal., ORF3 is a supplemental open reading frame coding for an accessory glycoprotein gp3 of unknown function, only present in genotype I canine strain (CCoV-I) and some atypical feline FCoV strains. In these latter hosts, the ORF3 gene systematically displays one or two identical deletions leading to the synthesis of truncated proteins gp3-Δ1 and gp3-Δ2. As deletions in CoV accessory proteins have already been involved in tissue or host switch, studies of these different gp3 proteins were conducted in canine and feline cell. All proteins oligomerise through covalent bonds, are N-glycosylated and are maintained in the ER in non-infected but also in CCoV-II infected cells, without any specific retention signal. However, deletions influence their level of expression. In canine cells, all proteins are expressed with similar level whereas in feline cells, the expression of gp3-Δ1 is higher than the two other forms of gp3. None of the gp3 proteins modulate the viral replication cycle of heterologous genotype II CCoV in canine cell line, leading to the conclusion that the gp3 proteins are probably advantageous only for CCoV-I and atypical FCoV strains.