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Objectives: Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD., Methods: This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort., Results: Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764)., Conclusions: Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population., Methods and Results: Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years [95% confidence interval (CI), 9.7-15.9] in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53-0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048)., Conclusion: HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Little is known about localized osteoarticular Scedosporiosis (LOS). Most data come from case reports and small case series. Here we present an ancillary study of the nationwide French Scedosporiosis Observational Study (SOS), describing 15 consecutive cases of LOS diagnosed between January 2005 and March 2017. Adult patients diagnosed with LOS defined by osteoarticular involvement without distant foci reported in SOS were included. Fifteen LOS were analyzed. Seven patients had underlying disease. Fourteen patients had prior trauma as potential inoculation. Clinical presentation was arthritis (n = 8), osteitis (n = 5), and thoracic wall infection (n = 2). The most common clinical manifestation was pain (n = 9), followed by localized swelling (n = 7), cutaneous fistulization (n = 7), and fever (n = 5). The species involved were Scedosporium apiospermum (n = 8), S. boydii (n = 3), S. dehoogii (n = 1), and Lomentospora prolificans (n = 3). The species distribution was unremarkable except for S. boydii, which was associated with healthcare-related inoculations. Management was based on medical and surgical treatment for 13 patients. Fourteen patients received antifungal treatment for a median duration of 7 months. No patients died during follow-up. LOS exclusively occurred in the context of inoculation or systemic predisposing factors. It has a non-specific clinical presentation and is associated with an overall good clinical outcome, provided there is a prolonged course of antifungal therapy and adequate surgical management., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Little is known about targeted (antiviral or monoclonal antibody) anti-SARS-CoV-2 treatment in immunocompromised patients with COVID-19., Objectives: To assess the real-life efficacy and tolerance of targeted treatment of COVID-19 in immunocompromised patients., Patients and Methods: Single-centre retrospective case series of immunocompromised patients with COVID-19 between December 2021 and March 2022. We recorded all cases of COVID-19 among immunocompromised patients treatment between 20 December 2021 and 15 March 2022. Choice of treatment was left to the physician's decision, according to internal treatment protocol, treatment availability and circulating variants. Main outcome was death from COVID-19 after no treatment or targeted treatment., Results: Sixty-seven immunocompromised patients [38 male; median (IQR) age, 53 (43-63) years], with a median (IQR) follow-up of 60 (47-80) days. Ten patients did not receive any targeted treatment. Targeted treatment consisted of IV curative remdesivir (n = 22), sotrovimab (n = 16), tixagevimab/cilgavimab (n = 13) and casirivimab/imdevimab (n = 1). Ten patients (15%) presented severe COVID-19 and 2 (3%) died from Omicron COVID-19. Comparing patients who received targeted anti-SARS-CoV-2 treatment and no prophylaxis, (n = 42; 81%) with those who did not (n = 10; 19%), death rate was significantly lower in treated patients [n = 0 (0%) versus n = 2 (20%); P = 0.034]. No severe adverse events were reported among treated patients. Among 15 patients who received tixagevimab/cilgavimab as pre-exposure prophylaxis, 6 received an additional curative treatment and none died from COVID-19., Conclusions: Our results suggest that targeted COVID-19 treatment, including direct antivirals or monoclonal antibodies, is safe and efficient and could be proposed in high-risk immunocompromised patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Heart transplantation (HT) and ventricular assist devices (VAD) for the management of end-stage heart failure have not been directly compared. We compare the outcomes and use of resources with these 2 strategies in 2 European countries with different allocation systems., Methods: We studied 83 patients managed by VAD as the first option in Bad Oeynhausen, Germany (Group I) and 141 managed with either HT or medical therapy, as the first option, in Paris, France (Group II). The primary end-point was 2-year survival. Kaplan-Meier analyses were performed after the application of propensity score weights to mitigate the effects of non-random group assignment. The secondary end-points were resource utilization and costs. Subgroup analyses were performed for patients undergoing HT and patients treated with inotropes at the enrolment time., Results: The Group I patients were more severely ill and haemodynamically compromised, and 28% subsequently underwent HT vs 55% primary HT in Group II, P < 0.001. The adjusted probability of survival was 44% in Group I vs 70% in Group II, P <0.0001. The mean cumulated 2-year costs were €281 361 ± 156 223 in Group I and €47 638 ± 35 061 in Group II, P < 0.0001. Among patients who underwent HT, the adjusted probability of survival in Group I (n = 23) versus Group II (n = 78) was 76% versus 68%, respectively (0.09), though it differed in the inotrope-treated subgroups (77% in Group I vs 67% in Group II, P = 0.04)., Conclusions: HT should remain the first option for end-stage heart failure patients, associated with improved outcomes and better cost-effectiveness profile. VAD devices represent an option when transplant is not possible or when patient presentation is not optimal., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Lung transplantation (LTx) is an accepted therapy for selected infants, children and adolescents with end-stage lung and pulmonary vascular disease. It remains a challenge for a selected group of patients. In 2011, the number of paediatric lung transplantations (PLTxs) worldwide was 107. In France, a total of 131 PLTxs have been performed since 2000 (data from ABM: Agence de biomédecine), 65 of which were conducted at our institution., Methods: All patients under 18 (4.8-17.11) years of age matching inclusion and exclusion criteria, who underwent LTx at our institution were included in this study (n = 58). We analysed the outcomes of these patients in terms of survival rates, controlling for indications for transplantations and surgical procedures. Secondary outcomes were analysis of surgical and medical complications and identification of prognostic factors in the field of LTx in these categories of ages., Results: The 30-day mortality rate was 10%. Kaplan-Meier survival rates at 1 month, 1, 3, 5 and 10 years were 90, 81, 66, 60 and 57%, respectively; the median survival was 91 months. Reduced-size transplantation was performed in 33% of double-lung transplantation (DLTx) patients without negatively impacting survival. In our series, female sex, the presence of a sex mismatching and, in particular, the occurrence of a male donor to a female recipient (F/M group) have been poor prognostic factors after PLTx., Conclusions: The overall survival after PLTx was encouraging (57% at 10 years). A PLTx should be offered to the small number of patients with end-stage pulmonary disease. The limited number of paediatric donor organs can be overcome by using reduced-size organs without a survival disadvantage to the patients. In our series, male sex and sex matching seemed to be positive predictive prognostic factors after PLTx but further studies are required to confirm these results and to also clarify the role of age of donor, time of cold ischaemia and body mass index in PLTx., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: To investigate the temporal trends in profile and outcomes of adults with congenital heart disease (ACHD) undergoing heart transplantation (HT)., Methods and Results: Out of a multi-institutional series of 2257 HT from 1988 to 2012, 100 HT were performed in 97 ACHD. We evaluated clinical characteristics, underlying defect, surgical history, perioperative issues, and outcomes. We compared two eras: era 1 (1988-2005, n = 48) and era 2 (2006-2012, n = 49). Mean age at HT was 30.3 ± 10.5 years. Twenty-five patients (25.8%) had biventricular physiology with a systemic right ventricle and 43 patients (44%) had univentricular physiology. Adults with congenital heart disease severity were classified as great complexity (74.2%), moderate (21.7%), and simple (4.1%). During a median follow-up of 28.7 months [0-282], 44 patients died. Early mortality was high (34%; 95% CI 0.2536-0.4390). Survival was 63.9% at 1 year. The proportion of univentricular patients did not change. Biventricular patients with systemic right ventricle significantly increased in era 2 (16.7  vs. 34.7%, P = 0.04) due to increasing number of transposition of the great arteries with atrial switch. Although the proportion of great complexity ACHD did not change significantly in era 2 (81.6%  vs. and 66.7% in era 1, P = 0.09), ACHD recipients have more advanced disease, being more likely hospitalized (P = 0.03), receiving intravenous inotropes (P = 0.01), under assist devices (P = 0.04), or UNOS status 1 (P = 0.02) at the time of HT. Survival rates were comparable., Conclusion: Despite a worse risk profile, mortality after HT in ACHD did not increase. Improving survival of complex CHD will probably amplify the proportion of complex ACHD recipients with more advanced disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells., Methods and Results: Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events., Conclusion: This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aim: Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection., Methods: We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity., Results: We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant., Conclusion: This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Aims: To report our experience with a left ventricular assist device axial pump as a bridge to transplantation: the DeBakey Ventricular Assist Device (VAD)., Methods: From February 1999 to February 2002, nine patients (among which eight males), with a mean age of 47 years, all in NYHA functional class IV, were proposed for a bridge to transplantation with the DeBakey VAD. Five patients had primary dilated cardiomyopathy, four had ischemic cardiomyopathy. All the patients had inotropic support prior to the intervention (dobutamine with a mean dose of 12 mcg/kg per min), six had an intra-aortic counterpulsation, four presented ventricular rhythm disorders. Interventions were performed through sternotomy alone (no need for an abdominal pocket) under extra-corporeal circulation on beating heart (except in one patient suffering from an apical thrombosis for which cardioplegic arrest was performed) as followed: implantation of the apical inflow cannula, tunneling of the percutaneous cable, implantation of the outflow graft under aortic side clamping, starting of the DeBakey VAD during CPB weaning-off., Results: Mean support duration was 81+/-62 days (16-224 days). Eight reoperations were required (three for bleeding or cardiac tamponade, one for haemoperitoneum, one for aortic bifurcation thrombectomy, one for right ventricular assist device implantation, two for iterative replacements of the DeBakey VAD). A significant hemolysis was observed in two patients. No device infection or dysfunction were observed. Secondary recovery of a pulsed flow was observed either clinically or by Echo-Doppler in six patients. Five patients were transplanted, four died prior to transplantation (three from multi-organ failure on post-operative day 35, 16 and 50, respectively, and the last patient was found disconnected at day 109)., Conclusions: The DeBakey VAD is at the origin of renewed interest for continuous flow assist devices. Still under evaluation, the advantages of miniaturization and facility of implantation of this new device seem to be promising.

Immunoglobulin abnormalities in serum from 76 heart-transplant recipients were examined by cellulose acetate and agarose gel electrophoresis. Monoclonal components were typed by immunofixation. IgG, IgA, and IgM and total kappa and lambda light chains were quantified by immunonephelometry. We confirm that both monoclonal and oligoclonal immunoglobulin banding are common in serum from these patients. Of the 149 serum samples examined, 21 (15%) had one monoclonal component and 53 (35%) had two or more. These monoclonal immunoglobulins were generally present at a low concentration and were transient. The class of immunoglobulins most commonly involved was IgG (about sevenfold more numerous than IgM); monoclonal IgA components and free light chains were not detected. The nephelometric kappa/lambda and heavy chain/light chain ratios were poor indicators of these abnormalities. Immunoglobulin abnormalities were not correlated with the sex and age of recipients, the pre-existing cardiopathy, the time since transplantation, or plasma concentrations of cyclosporine, but did correlate with plasma immunoglobulin concentration, biopsy findings, and viral infections, especially cytomegalovirus (CMV). A monoclonal IgG purified from a patient with a high titer of anti-CMV antibodies did not react with CMV antigens. The origin of these immunoglobulin abnormalities is unclear. Our data suggest that the presence of monoclonal or oligoclonal banding in heart-transplant recipients is of limited prognostic significance.