A Slug Flow Platform with Multiple Process Analytics Facilitates Flexible Reaction Optimization.

Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low-volume optimization experiments are reported. A Buchwald-Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self-optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor.

High resolution mapping of the tumor microenvironment using integrated single-cell, spatial and in situ analysis.

Single-cell and spatial technologies that profile gene expression across a whole tissue are revolutionizing the resolution of molecular states in clinical samples. Current commercially available technologies provide whole transcriptome single-cell, whole transcriptome spatial, or targeted in situ gene expression analysis. Here, we combine these technologies to explore tissue heterogeneity in large, FFPE human breast cancer sections. This integrative approach allowed us to explore molecular differences that exist between distinct tumor regions and to identify biomarkers involved in the progression towards invasive carcinoma. Further, we study cell neighborhoods and identify rare boundary cells that sit at the critical myoepithelial border confining the spread of malignant cells. Here, we demonstrate that each technology alone provides information about molecular signatures relevant to understanding cancer heterogeneity; however, it is the integration of these technologies that leads to deeper insights, ushering in discoveries that will progress oncology research and the development of diagnostics and therapeutics.

Donor heart selection: Evidence-based guidelines for providers.

The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review.

Custodiol-N versus Custodiol: a prospective randomized double-blind multicentre phase III trial in patients undergoing elective coronary bypass surgery.

OBJECTIVES: HTK-Solution (Custodiol) is a well-established cardioplegic and organ preservation solution. We currently developed a novel HTK-based solution, Custodiol-N, which includes iron chelators to reduce oxidative injury, as well as l-arginine, to improve endothelial function. In this first-in-human study, Custodiol-N was compared to Custodiol in patients undergoing elective coronary artery bypass surgery. The aim of this comparison was to evaluate the safety and ability of Custodiol-N to protect cardiac tissue. METHODS: The study was designed as a prospective randomized double-blind non-inferiority trial. Primary end point was area under the curve (AUC) of creatine kinase muscle-brain (CK-MB) within the first 24 h after surgery. Secondary end points included peak CK-MB and troponin-T and AUC of troponin-T release, cardiac index, cumulative catecholamine dose, intensive care unit stay and mortality. All values in the abstract are given as mean ± SD, P < 0.05 was considered statistically significant. RESULTS: Early termination of the trial was performed per protocol as the primary non-inferiority end-point was reached after inclusion of 101 patients. CK-MB AUC (878±549 vs 779±439 h U/l, non-inferiority P < 0.001, Custodiol vs Custodiol-N) and troponin-T AUC (12990±8347 vs 13498±6513 h pg/ml, noninferiority P < 0.001, Custodiol vs Custodiol-N) were similar in both groups. Although the trial was designed for non-inferiority, peak CK-MB (52±40 vs 42±28 U/l, superiority P < 0.03, Custodiol vs Custodiol-N) was significantly lower in the Custodiol-N group. CONCLUSIONS: This study shows that Custodiol-N is safe and provides similar cardiac protection as the established HTK-Custodiol solution. Significantly reduced peak CK-MB levels in the Custodiol-N group in the full analysis set may implicate a beneficial effect on ischaemia/reperfusion injury in the setting of coronary bypass surgery.

[Somatic dysfunction of the cervical spine and its complex clinical picture : The fundamentals of diagnostics of cervicobrachialgia and cervicocephalic syndrome through manual medicine]. / Die somatische Dysfunktion der Halswirbelsäule und ihr komplexes klinisches Bild : Grundlagen der manualmedizinischen Diagnostik von Zervikobrachialgie und zervikozephalem Syndrom.

Patients suffering from a segmental and somatic dysfunction of the cervical spine often present a wide variety of clinical symptoms related to cervicobrachial or cervicocephalic syndrome. These symptoms might evolve out of complex neural intersegmental or trigeminocervical interactions in the brain stem or the spinal cord of the cervical spine. After the exclusion of life-threatening preconditions, a careful physical examination with aspects of manual medicine aspects might unmask the cervical dysfunction as the primary cause of the symptoms. Treatment with manual medicine on the basis of a segmental antinociceptive proprioceptive input might then be an appropriate therapeutic approach.

[Segmental and somatic dysfunction : How does manual medicine work?] / Die segmentale und somatische Dysfunktion : Wie funktioniert Manuelle Medizin?

BACKGROUND: Manual medicine is based on neurophysiologic and biomechanical principles. Impaired senso-motor regulation causes segmental and somatic dysfunction. Via segmental mapping, somato-sensory and vegetative dysfunction arises. Local pain, referred pain, and vague symptoms can occur in the thoracic and abdominal regions. Myofascial structures can transfer these dysfunctions to other body areas, where segmental neuronal connections lead to further dysfunction. Manual medicine addresses these aspects. TECHNIQUES: Manual interventions work by influencing the proprioceptive system, improving senso-motor regulation. Furthermore, proprioceptive stimulation inhibits pain mechanisms in the CNS (spinal and cerebral). Manual techniques may focus on joints, myofascial, or visceral structures. The main common target is to induct proprioceptive stimulus into related spinal segments. PATHOLOGY: Knowledge of these neurophysiologic and biomechanical aspects can be a powerful tool in differential diagnostics, particularly in cases of apparently inconsistent clinical findings. Additionally, structural pathology can lead to reflex-mediated dysfunction. To determine whether structural pathology or functional derangement is accountable for symptomatology, a manual approach on a trial basis can be very helpful. Lege artis indicated and performed, manual medicine offers an excellent risk-benefit ratio.

[Manual medicine for the extremity joints : Successful treatment of complex symptom constellations]. / Manuelle Medizin an den Extremitätengelenken : Komplexe Symptomkonstellationen erfolgreich behandeln.

One important field of manual medicine is the special diagnosis and treatment of the extremities. Biomechanical and neurophysiologic knowledge allows identification and treatment of so-called kinetic chain syndromes. The manual diagnosis of the extremities follows clear criteria and enables the diagnosis of myofascial or joint dysfunction. The manual approach to the extremities has many parallels with spinal treatment, although in certain cases, it follows a distinct algorithm. This article addresses the manual diagnosis and treatment of the joints of the extremities. Three case reports demonstrate how symptoms and manual findings guide manipulative treatment and what impact this can have.

A Report on the First 7 Sequential Patients Treated Within the C-Reactive Protein Apheresis in COVID (CACOV) Registry.

BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonia is a disease with high mortality and, still, no effective treatment. Excessively elevated C-reactive protein (CRP) plasma levels inversely correlate with prognosis. As CRP, via complement and macrophage activation, can cause organ damage in COVID-19, we have recently introduced selective CRP apheresis as a potentially effective treatment. Now, we report on the first patients with severe SARS-CoV-2-induced pneumonia treated within the "C-reactive protein Apheresis in COVID" (CACOV) registry. CASE REPORT Seven sequential hospitalized patients with documented COVID-19, strongly elevated CRP plasma levels, and respiratory failure were treated by selective CRP apheresis in addition to standard therapy after having given their informed consent for inclusion in the CACOV registry. We performed 2-8 CRP apheresis sessions via either peripheral or central venous access depending on clinical course and CRP plasma levels. CRP apheresis, in COVID-19, reduced CRP plasma levels by approximately 50-90%, and it was thus highly effective, feasible, and safe. Despite severe radiological lung involvement in all our patients, only 2 patients finally required intubation, and none required extracorporeal membrane oxygenation (ECMO). All 7 patients were discharged from our 2 hospitals in good clinical condition. CONCLUSIONS Selective CRP apheresis, starting early after patient admission, may be an effective treatment of SARS-CoV-2-induced pneumonia. SARS-COV-2 can cause organ damage and multiple organ failure predominantly by an excessive CRP-mediated autoimmune response of the ancient innate immune system. Further registry data and randomized trials are needed.

Bone formation after surgically assisted rapid maxillary expansion: comparison of 2 distraction osteogenesis protocols.

OBJECTIVE: The aim of this study was to compare bone formation between 2 distraction osteogenesis protocols by analyzing cone beam computed tomography (CBCT) scan data. STUDY DESIGN: In this retrospective study, the efficacy of 2 different surgically assisted rapid maxillary expansion protocols (group 1 [G1], 3 × 0.25 mm/d; group 2 [G2], 1 mm start followed by 2 × 0.25 mm/d) was analyzed using CBCT scans obtained at 3 time points: preoperatively (T0), immediately after surgery (T1), and 6 months after surgery (T2). Bone formation at T0, T1, and T2 was analyzed using the Dolphin Imaging 11 program. RESULTS: At T1, both groups had significantly higher bone volume than at T0 (G1, 135.6 vs 124.65 mm3, respectively; G2, 153.49 vs 118.9 mm3, respectively), with no significant difference between groups (P = .6). Moreover, bone density measured in the region of interest was similar between groups at all 3 time points; however, in both groups, bone density was significantly lower at T1 and T2 than at T0 (P < .01), with no difference between T1 and T2. CONCLUSIONS: Bone density between the incisors decreased with progressive distraction (i.e., increasing volume), regardless of the distraction protocol used; thus, both protocols can be used safely in clinical practice. Nevertheless, our results indicate that stress should not be applied to the incisors within 6 months of surgery, regardless of the protocol used. Surgeons and orthodontists should therefore consider immature bone formation and avoid using excessive force to close a diastema.

Successful Treatment of a 39-Year-Old COVID-19 Patient with Respiratory Failure by Selective C-Reactive Protein Apheresis.

BACKGROUND High C-reactive protein (CRP) plasma levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with poor prognosis. CRP, by activating the classical complement pathway and interacting with macrophages via Fc gamma receptors, can cause pulmonary inflammation with subsequent fibrosis. Recently, we have reported first-in-man CRP apheresis in a "high-risk" COVID-19 patient. Treatment was unfortunately clinically unsuccessful. Here, we report on successful CRP apheresis treatment in a "lower-risk" COVID-19 patient with respiratory failure. CASE REPORT A 39-year-old male patient suffering from fatigue, dyspnea, and fever for 4 days was referred to us. The patient had to be intubated. Polymerase chain reaction (PCR) analysis of a throat smear revealed SARS-CoV-2 infection. Mutation analysis revealed the VOC B. 1.1.7 variant. CRP levels were 79.2 mg/L and increased to 161.63 mg/L. Procalcitonin (PCT) levels were continuously normal (<0.5 ng/ml). Antibiotic therapy was started to avoid bacterial superinfection. CRP apheresis was performed once via central venous access. CRP levels declined from a maximum of 161.63 mg/L to 32.58 mg/L. No apheresis-associated adverse effects were observed. Subsequently, CRP plasma levels declined day by day and normalized on day 5. The patient was extubated on day 5 and discharged from the Intensive Care Unit (ICU) on day 6. A second low CRP peak (maximum 22.41 mg/L) on day 7 remained clinically inapparent. The patient was discharged in good clinical condition with a CRP level of 6.94 mg/L on day 8. CONCLUSIONS SARS-CoV-2 infection can induce an uncontrolled CRP-mediated autoimmune response of ancient immunity. In this patient, the autoimmune response was potently and successfully suppressed by early selective CRP apheresis.

Characterization of an ETV6-NTRK3 rearrangement with unusual, but highly significant FISH signal pattern in a secretory carcinoma of the salivary gland: a case report.

BACKGROUND: Fusions of neurotrophic tropomyosin receptor kinase genes NTRK1, NTRK2 and NTRK3 with various partner genes occur in both common and rare tumours and are of paramount predictive value due to the availability of very effective pan-Trk inhibitors like Larotrectinib and Entrectinib. Detection of NTRK fusions is mainly performed by fluorescence in situ hybridization (FISH) and next generation sequencing (NGS). The case described here showed a very unusual, but highly significant FISH signal pattern with an NTRK3 break apart probe, indicative of a functional NTRK3 rearrangement. CASE PRESENTATION: We describe here the case of a male patient who was originally diagnosed with an adenocarcinoma of the parotid gland without evidence of metastases. After the development of multiple lung metastases, an extensive immunohistochemical and molecular examination of archived tumour tissue including analysis of NTRK was performed. NTRK expression was detected by immunohistochemistry (IHC) and then comprehensively analysed further by FISH, quantitative reverse transcription PCR (RT-qPCR), and NGS. NTRK3 break apart FISH showed multiple and very faint single 3' signals in addition to fusion signals. Quantitative reverse transcription PCR and NGS confirmed an ETV6:exon5-NTRK3:exon15 fusion. Diagnosis was therefore revised to metastatic secretory carcinoma of the salivary gland, and the patient subsequently treated with Larotrectinib, resulting in persisting partial remission. CONCLUSIONS: Our findings underline the importance to be aware of non-canonical signal patterns during FISH analysis for detection of NTRK rearrangements. Very faint single 3' signals can indicate a functional NTRK rearrangement and therefore be of high predictive value.

[Preparing for a pandemic]. / Vorbereitungen auf eine pandemische Welle.

On 16 March 2020 the government of Bavaria declared a state of emergency due to the coronavirus disease 2019 (COVID-19) pandemic. This confronted all clinics with completely new and difficult challenges. In accordance with the official requirements, pandemic officers were appointed at the Kempten Clinic and a clinical management team was established. It was important to keep a relevant proportion of employees off duty at all times, and thus to have a constant reserve available in the event of expected infection-related absences of physicians and nurses. These structural changes were complemented by staff briefings and the creation of a training program on the subject of COVID-19. Within a very short time, algorithms were designed and defined how to manage patients presenting in the hospital or in the emergency room. The surgical program was limited to operations that could not be postponed, such as extrauterine pregnancy or adnexal torsion, and oncological diagnoses without the possibility of primary systemic therapy. In the case of breast cancer, however, therapy was started in all cases in which primary systemic therapy (PST), whether cytotoxic or endocrinological, appeared possible and indicated. As of 1 April 2020, more than 50% of the usable beds in the Kempten Clinic were empty. The utilization of the intensive care unit had also been reduced so that higher numbers of patients requiring artificial respiration could have been cared for at any time.

Quantifying the environmental impact of clustering strategies in waste management: A case study for plastic recycling from large household appliances.

The complex composition of waste electrical and electronic equipment (WEEE) plastics represents a challenge during post-consumption plastic recycling. A single WEEE category, e.g. large household appliances (LHA), can contain several different plastic types with overlapping material properties, making the sorting of individual plastics a challenge. Significant increases in plastic recovery rates can be expected by clustering product categories, as clustering can avoid mixing of non-compatible plastics with overlapping material properties. For this purpose, a life cycle assessment (LCA) is conducted to investigate the influence of different clustering strategies on the environmental performance of waste treatment and the production of recycled plastic from LHA waste stream. To assure comparability between waste treatment scenarios a system expansion approach is applied, and to allocate the burden of shared processes over the first and second use cycle of the material partitioning is applied. Results show that an increased separation of product clusters by plastic type can improve the plastic recovery rate from 5.8% to 47.1% and reduce the overall environmental impact, quantified with the ReCiPe (2016) method, by up to 23%. The environmental impacts of using recycled plastics from LHA waste can be reduced by 27 to 38% compared to single-use plastic. The holistic approach used in this study demonstrates (1) the potential benefits of implementing product clustering strategies for LHA plastic recycling, (2) the relevance of different allocation procedures when integrating recycling into an LCA, (3) the importance of using less virgin material and avoiding final waste treatment, and (4) the limitation of the recycling system to reduce the environmental burden associated with products.

Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice.

PURPOSE: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail. MATERIAL AND METHODS: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (60Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125, and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous Ercc2 mutant mice were used and compared to wild-type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 h, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 h as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen. RESULTS: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts (PSCs) 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95% confidence interval 2.1-41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of PSCs at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect. CONCLUSIONS: This article demonstrates a significant radiation-induced increase in the incidence of PSCs, which could not be identified using Scheimpflug imaging as the only diagnostic tool.

Should concomitant surgical ablation for atrial fibrillation be performed in elderly patients?

OBJECTIVE: The incidence of atrial fibrillation increases with age, and therefore many elderly patients presenting for cardiac surgery have atrial fibrillation. In recent publications, increasing age has been recognized as a predictor for ablation failure. Furthermore, many surgeons are reluctant to perform a surgical ablation in elderly patients. We investigated the safety and efficacy of concomitant surgical atrial fibrillation ablation in elderly patients. METHODS: Between 2003 and 2013, 556 patients underwent concomitant surgical atrial fibrillation ablation at the University Heart Center Hamburg and served as our primary study cohort. During follow-up, rhythm monitoring was established by 24-hour Holter electrocardiogram (70.5%) or an implantable loop recorder (29.5%) at 3, 6, and 12 months postoperatively. The primary end point of the study was freedom from atrial fibrillation at 12 months follow-up and the detection of deviations from a linear association between age and risk of atrial fibrillation recurrence. A multiple logistic regression model including age as a linear term was used to identify predictors for rhythm outcome. RESULTS: Mean patients' age was 68.4 ± 9.07 years, and 67.3% of the patients were male. Mean duration of atrial fibrillation was 3.5 ± 3.3 years, and mean left atrium diameters were enlarged with 50.5 ± 8.8 mm. There were no major ablation-related complications. The 30-day and 1-year survivals were 97.7% and 95.8%, respectively. The overall rate of freedom from atrial fibrillation ranged from 62% to 72% and was independent of age. The age-dependent risk of atrial fibrillation at 12 months was significantly increased in elderly patients undergoing a concomitant coronary artery bypass grafting surgery. Multiple logistic regression model revealed double valve procedures (odds ratio, 3.48; P = .020), preoperative persistent atrial fibrillation (odds ratio, 2.43; P = .001), and coronary artery bypass grafting surgery in elderly patients (odds ratio, 2.03; P = .009) as risk factors for recurrence of atrial fibrillation. Sinus rhythm at discharge (odds ratio, 0.39; P < .001) and bipolar ablation (odds ratio, 0.32; P < .001) were significant predictors for successful ablation. CONCLUSIONS: Surgical atrial fibrillation ablation was safe and effective independently of age. Sinus rhythm at discharge and bipolar ablation were significant predictors for successful ablation, whereas double valve procedures, preoperative persistent atrial fibrillation, and coronary artery bypass grafting surgery in elderly patients were risk factors for recurrence of atrial fibrillation.

Dose-dependent long-term effects of a single radiation event on behaviour and glial cells.

PURPOSE: The increasing use of low-dose ionizing radiation in medicine requires a systematic study of its long-term effects on the brain, behaviour and its possible association with neurodegenerative disease vulnerability. Therefore, we analysed the long-term effects of a single low-dose irradiation exposure at 10 weeks of age compared to medium and higher doses on locomotor, emotion-related and sensorimotor behaviour in mice as well as on hippocampal glial cell populations. MATERIALS AND METHODS: We determined the influence of radiation dose (0, 0.063, 0.125 or 0.5 Gy), time post-irradiation (4, 12 and 18 months p.i.), sex and genotype (wild type versus mice with Ercc2 DNA repair gene point mutation) on behaviour. RESULTS: The high dose (0.5 Gy) had early-onset adverse effects at 4 months p.i. on sensorimotor recruitment and late-onset negative locomotor effects at 12 and 18 months p.i. Notably, the low dose (0.063 Gy) produced no early effects but subtle late-onset (18 months) protective effects on sensorimotor recruitment and exploratory behaviour. Quantification and morphological characterization of the microglial and the astrocytic cells of the dentate gyrus 24 months p.i. indicated heightened immune activity after high dose irradiation (0.125 and 0.5 Gy) while conversely, low dose (0.063 Gy) induced more neuroprotective features. CONCLUSION: This is one of the first studies demonstrating such long-term and late-onset effects on brain and behaviour after a single radiation event in adulthood.

Author Correction: Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas.

A Correction to this paper has been published: https://doi.org/10.1038/s41587-019-0392-8.

ALLCOPOL: inferring allele co-ancestry in polyploids.

BACKGROUND: Inferring phylogenetic relationships of polyploid species and their diploid ancestors (leading to reticulate phylogenies in the case of an allopolyploid origin) based on multi-locus sequence data is complicated by the unknown assignment of alleles found in polyploids to diploid subgenomes. A parsimony-based approach to this problem has been proposed by Oberprieler et al. (Methods Ecol Evol 8:835-849, 2017), however, its implementation is of limited practical value. In addition to previously identified shortcomings, it has been found that in some cases, the obtained results barely satisfy the applied criterion. To be of better use to other researchers, a reimplementation with methodological refinement appears to be indispensable. RESULTS: We present the AllCoPol package, which provides a heuristic method for assigning alleles from polyploids to diploid subgenomes based on the Minimizing Deep Coalescences (MDC) criterion in multi-locus sequence datasets. An additional consensus approach further allows to assess the confidence of phylogenetic reconstructions. Simulations of tetra- and hexaploids show that under simplifying assumptions such as completely disomic inheritance, the topological errors of reconstructed phylogenies are similar to those of MDC species trees based on the true allele partition. CONCLUSIONS: AllCoPol is a Python package for phylogenetic reconstructions of polyploids offering enhanced functionality as well as improved usability. The included methods are supplied as command line tools without the need for prior programming knowledge.

International experience using a durable, centrifugal-flow ventricular assist device for biventricular support.

BACKGROUND: Heart transplantation is limited by the scarcity of suitable donors. Patients with advanced biventricular failure may require biventricular support to provide optimal cardiac output and end-organ perfusion. We highlight the outcomes of using the HeartWare HVAD System (HVAD) in a biventricular configuration. METHODS: This retrospective study included patients implanted with HVAD as a biventricular assist device (BiVAD) between 2009 and 2017 at 12 participating centers. When used as a right ventricular assist device (VAD) (RVAD), the HVAD can be attached to the right ventricle (RV) or the right atrium (RA). Kaplan-Meier survival estimates were calculated comparing the 2 RVAD implant locations. Comparisons were also made between the timing of RVAD implantation (primary vs staged) on adverse event (AE) profiles and survival. RESULTS: Among the 93 patients who were implanted with a HVAD BiVAD, Kaplan-Meier survivals at 1-year and 2-year were 56% and 47%, respectively. Survival was independent of the location of the HVAD RVAD implant or whether there was an interval between left VAD and RVAD implantation. The most common AEs were bleeding (35.5%), infection (25.8%), and respiratory failure (20.4%). CONCLUSIONS: This study illustrated similar survival in patients receiving a primary or staged HVAD BiVAD implant at 1 year and 2 years. This study also established that the locations of the RVAD implant (RV or RA) result in similar AE profiles.

Clinical characteristics and outcomes of patients with adult congenital heart disease listed for heart and heart‒lung transplantation in the Eurotransplant region.

BACKGROUND: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation. METHODS: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes. RESULTS: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years. CONCLUSIONS: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list.