Pregnancy in women with a Fontan circulation: Short and long-term outcomes.

BACKGROUND: The Fontan circulation procedure is the palliative surgery of choice for patients with single ventricle physiology, many of whom are now reaching childbearing age due to advances in care. Our study examines the impact of pregnancy on women with Fontan circulation, assessing both short and long-term outcomes. METHODS: We retrospectively analysed pregnancies in women with Fontan circulation at our centre from 2005 to 2023, including a matched non-pregnant, nulliparous cohort for comparison. Pregnancies lost before 18 weeks were analysed separately. RESULTS: Among 26 pregnancies in 18 women, preterm births were common (73.1%), with 3 fetal losses and no maternal deaths. Neonatal complications included a 50% incidence of babies small for gestational age (SGA). Cardiac events occurred in 19.2% of pregnancies, primarily supraventricular arrhythmias, and 23% experienced postpartum haemorrhage. Over a median 6.1 [5.2-10.6]-year follow-up, no deaths, heart failure (HF), or Fontan-associated liver disease (FALD) developed, and functional status remained stable. CONCLUSIONS: Women with a Fontan-type circulation undergoing pregnancy had a few serious maternal cardiac events, though there was a high rate of post-partum haemorrhage. The rates of neonatal complications, particularly related to restricted growth and pre-term birth, were also high. Our findings indicate a generally positive medium-term outlook for these patients, though the impact of pregnancy on long-term survival remains unclear. Careful selection of patients with Fontan circulation during pre-pregnancy counselling may help to reduce complications during and after pregnancy.

Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium.

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Morbidity and mortality in adults with a Fontan circulation beyond the fourth decade of life.

AIMS: To evaluate the late outcomes of adults (above 35 years) with a Fontan-type circulation, for whom current data on morbidity and mortality are lacking. METHODS AND RESULTS: Data were collected retrospectively on consecutive patients with Fontan circulation above the age of 35 years followed in three European specialist centres. Overall, 115 Fontan patients were included [median age 35 (range 35-48) years, 47.8% female]. The most common underlying congenital heart disease diagnosis was tricuspid atresia (n = 58, 50.4%), and the age at first Fontan completion was 9.1 (interquartile range 5.0-15.8) years. Almost two-thirds (61.7%) of patients had undergone an atriopulmonary Fontan, and 23.5% had received a total cavopulmonary connection. One-third required repeat surgery or intervention. Most patients (55.9%) were in New York Heart Association functional class II or class I (30.6%), 76 (66.1%) patients had experienced at least one arrhythmia, and eight (7.0%) protein-losing enteropathy. At a median follow-up of 5.0 (2.4-10.3) years, 15 (13.0%) patients were referred for transplantation assessment and 19 (16.5%) patients died, mainly from heart failure (84.2%). Univariable predictors of death or transplantation included lower serum albumin level [hazard ratio (HR) 1.09 per g/L decrease, 95% confidence interval (CI): 1.04-1.15, P = 0.0009], prior heart failure admission (HR 4.28, 95% CI:1.75-10.44, P = 0.001), prior atrial tachycardia or flutter (HR 3.02, 95% CI: 1.23-7.38, P = 0.02), and baseline pulmonary vasodilator therapy (HR 8.59, 95% CI:1.05-70.13, P = 0.04). Lower serum albumin and prior atrial tachycardia or flutter remained significant on bivariable analysis. CONCLUSION: Our study highlights the significant morbidity and mortality in older adults with a Fontan-type circulation, emphasizing the need for lifelong specialist surveillance with frequent risk stratification, close monitoring, and early consideration for transplantation assessment.

This study sheds light on the complex medical journey of adults living with the outcomes of Fontan surgery­a procedure performed in early childhood. These individuals have reached the milestone of their forties and beyond, yet they confront an array of significant health challenges that necessitate lifelong, individualized congenital heart disease care. The key findings are as follows:While adults with Fontan circulation are living longer, they are at high risk of death, mainly due to heart failure. They also face a host of other health issues, including the need for additional surgeries or interventions. Nearly two-thirds have experienced some form of heart rhythm problem, and a substantial number eventually require evaluation for a heart transplant.Heart transplants within this group were rare, which may be linked to the various barriers to transplantation in the Fontan population. Moreover, those with multiple indicators of advanced disease have a heightened risk of life-threatening events, reinforcing the critical need for personalized and continuous specialist care designed to meet their distinct health requirements.

Repair of Aortic Regurgitation in Young Adults: Sooner Rather Than Later.

Background Establishing surgical criteria for aortic valve replacement (AVR) in severe aortic regurgitation in young adults is challenging due to the lack of evidence-based recommendations. We studied indications for AVR in young adults with severe aortic regurgitation and their outcomes, as well as the relationship between presurgical echocardiographic parameters and postoperative left ventricular (LV) size, function, clinical events, and valve-related complications. Methods and Results Data were collected retrospectively on 172 consecutive adult patients who underwent AVR or repair for severe aortic regurgitation between 2005 and 2019 in a tertiary cardiac center (age at surgery 29 [22-41] years, 81% male). One-third underwent surgery before meeting guideline indications. Postsurgery, 65% achieved LV size and function normalization. LV ejection fraction showed no significant change from baseline. A higher presurgical LV end-systolic diameter correlated with a lack of LV normalization (odds ratio per 1-cm increase 2.81, P<0.01). The baseline LV end-systolic diameter cut-off for predicting lack of LV normalization was 43 mm. Pre- and postoperative LV dimensions and postoperative LV ejection fraction predicted clinical events during follow-up. Prosthetic valve-related complications occurred in 20.3% during an average 5.6-year follow-up. Freedom from aortic reintervention was 98%, 96.5%, and 85.4% at 1, 5, and 10 years, respectively. Conclusions Young adult patients with increased baseline LV end-systolic diameter or prior cardiac surgery are less likely to achieve LV normalization after AVR. Clinicians should carefully balance the long-term benefits of AVR against procedural risks and future interventions, especially in younger patients. Evidence-based criteria for AVR in severe aortic regurgitation in young adults are crucial to improve outcomes.

ProGraME: A novel flow cytometry algorithm for the diagnosis of low-risk myelodysplastic syndromes in patients with cytopenia.

OBJECTIVES: Flow cytometry (FC) is, together with morphology, genetics, and cytogenetics, used in the diagnostic assessment of cytopenia, as its value in evaluating bone marrow dysplasia been highlighted by several studies. However, despite the development of algorithms and guidelines, there is still a lack of standardization of the FC assessment of bone marrow dysplasia. METHODS: By combining FC, together with morphological analysis and cytogenetic/molecular assessment in a training cohort of 209 patients, we created a novel score, ProGraME, which includes four parameters, each from a different cell lineage (Progenitor cells, Granulocytes, Monocytes, Erythroid precursors), solely based on relevant population gating. Points for ProGraME were attained for: lymphoid precursors ≤5% of all CD34+ cells (1.5 point); a granulocyte-to-lymphocyte side-scatter ratio ≤6 (1 point); a monocyte CD33-CV% ≥ 63 (2 points), and an erythroid precursor CD36-CV% ≥ 65 (2 points). RESULTS: Using a cutoff of ≥2 as suggestive of dysplasia, ProGraME showed a sensitivity of 91% and a specificity of 81% in the training cohort and 95% and 75%, respectively, in an independent validation cohort of 159 patients. In addition, ProGraME had a very high negative predictive value of 97.1% and 97.8% in the training and validation cohorts, respectively, offering a useful tool for excluding bone marrow dysplasia. Finally, among the 23 CCUS patients that scored positive for dysplasia with ProGraME in the training cohort, 16 of them (69%) carried high-risk mutations, suggesting that FC might help identify early changes of dysplasia. CONCLUSIONS: ProGraME can potentially optimize the FC diagnosis of low-risk myelodysplasia without minimal requirements of flow analysis other than accurate population gating.

Concurrent Inhibition of Akt and ERK Using TIC-10 Can Overcome Venetoclax Resistance in Mantle Cell Lymphoma.

Venetoclax, a BCL-2 inhibitor, has proven to be effective in several hematological malignancies, including mantle cell lymphoma (MCL). However, development of venetoclax resistance is inevitable and understanding its underlying molecular mechanisms can optimize treatment response. We performed a thorough genetic, epigenetic and transcriptomic analysis of venetoclax-sensitive and resistant MCL cell lines, also evaluating the role of the stromal microenvironment using human and murine co-cultures. In our model, venetoclax resistance was associated with abrogated TP53 activity through an acquired mutation and transcriptional downregulation leading to a diminished apoptotic response. Venetoclax-resistant cells also exhibited an upregulation of the PI3K/Akt pathway, and pharmacological inhibition of Akt and ERK with TIC-10 led to cell death in all venetoclax-resistant cell lines. Overall, we highlight the importance of targeted therapies, such as TIC-10, against venetoclax resistance-related pathways, which might represent future therapeutic prospects.

Inflammatory Cytokine Profiles Do Not Differ Between Patients With Idiopathic Cytopenias of Undetermined Significance and Myelodysplastic Syndromes.

Immune dysregulation has been highlighted as a key player in the pathogenesis of myelodysplastic syndromes (MDS), but little is known about cytokine profiles in patients with unexplained cytopenia with or without mutations in MDS-associated genes (clonal cytopenias of undetermined significance [CCUS] and idiopathic cytopenias of undetermined significance [ICUS], respectively), which often precede MDS. Here, we study the cytokine profiles in 111 patients with ICUS (N = 41), CCUS (N = 30), lower-risk MDS (LR-MDS; N = 22) and higher-risk MDS (HR-MDS; N = 18), and in healthy elderly controls (N = 21). Twenty cytokines were examined in blood plasma at time of diagnosis using Luminex assays and enzyme linked immunosorbent assays. The cytokine levels were compared between patient groups, and in patients versus controls. Associations between cytokines and MDS-associated mutations were evaluated. An aberrant cytokine profile was observed in all patient groups relative to healthy elderly controls. Patients had significantly higher levels of IL-6 (P< 0 .001), tumor necrosis factor α (P < 0.001), IL-10 (P < 0.001), and C-X-C motif chemokine 10 (P < 0.001) and lower levels of transforming growth factor beta 1 (P < 0.001), CCL5/regulated on activation normal T-cell expressed and secreted (P < 0.001), and S100A4 (P < 0.001) compared with healthy controls. Survival was significantly shorter in CCUS and MDS patients with a high systemic inflammatory cytokine load (median overall survival [OS] 21 months) compared with those with low-moderate systemic inflammatory cytokine load (median OS 64 months; P < 0.0001). These data suggest that patients with ICUS and CCUS have cytokine levels as abnormal as in LR-MDS. Indeed, high cytokine levels are present before MDS is diagnosed and cytokine levels are elevated irrespective of the presence or size of the myeloid clones. Cytokines may have a prognostic impact at a very early premalignant stage of myeloid disorders.

Eisenmenger Syndrome: JACC State-of-the-Art Review.

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension-targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond.

Comprehensive and unbiased multiparameter high-throughput screening by compaRe finds effective and subtle drug responses in AML models.

Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.

Biology has seen huge advances in technology in recent years. This has led to state-of-the-art techniques which can test hundreds of conditions simultaneously, such as how cancer cells respond to different drugs. In addition to this, each of the tens of thousands of cells studied can be screened for multiple variables, such as certain proteins or genes. This generates massive datasets with large numbers of parameters, which researchers can use to find similarities and differences between the tested conditions. Analyzing these 'high-throughput' experiments, however, is no easy task, as the data is often contaminated with meaningless information, or 'background noise', as well as sources of bias, such as non-biological variations between experiments. As a result, most analysis methods can only probe one parameter at a time, or are unautomated and require manual interpretation of the data. Here, Chalabi Hajkarim et al. have developed a new toolkit that can analyze multiparameter datasets faster and more robustly than current methods. The kit, which was named 'compaRe', combines a range of computational tools that automatically 'clean' the data of background noise or bias: the different conditions are then compared and any similarities are visually displayed using a graphical interface that is easy to explore. Chalabi Hajkarim et al. used their new method to study data from patients with acute myeloid leukemia (AML) and myelodysplastic syndrome, two forms of cancer that disrupt the production of functional immune cells. The toolkit was able to identify subtle differences between the patients and categorize them into groups based on the proteins present on immune cells. Chalabi Hajkarim et al. also applied compaRe to high-throughput data on cells from patients and mouse models with AML that had been treated with large numbers of specific drugs. This revealed that different cell types in the samples responded to the treatments in distinct ways. These findings suggest that the toolkit created by Chalabi Hajkarim et al. can automatically, rapidly and precisely compare large multiparameter datasets collected using high-throughput screens. In the future, compaRe could be used to identify drugs that illicit a specific response, or to predict how newly developed treatments impact different cell types in the body.

Use of Pulmonary Arterial Hypertension Therapies in Patients with a Fontan Circulation: Current Practice Across the United Kingdom.

Background The Fontan circulation is a successful operative strategy for abolishing cyanosis and chronic volume overload in patients with congenital heart disease with single ventricle physiology. "Fontan failure" is a major cause of poor quality of life and mortality in these patients. We assessed the number and clinical characteristics of adult patients with Fontan physiology receiving pulmonary arterial hypertension (PAH) therapies across specialist centers in the United Kingdom. Methods and Results We identified all adult patients with a Fontan-type circulation under active follow-up in 10 specialist congenital heart disease centers in England and Scotland between 2009 and 2019. Patients taking PAH therapies were matched to untreated patients. A survey of experts was also performed. Of 1538 patients with Fontan followed in specialist centers, only 76 (4.9%) received PAH therapies during follow-up. The vast majority (90.8%) were treated with a phosphodiesterase-5 inhibitor. In 33% of patients, PAH therapies were started after surgery or during hospital admission. In the matched cohort, treated patients were more likely to be significantly limited, have ascites, have a history of protein-losing enteropathy, or receive loop diuretics (P<0.0001 for all), also reflecting survey responses indicating that failing Fontan is an important treatment target. After a median of 12 months (11-15 months), functional class was more likely to improve in the treated group (P=0.01), with no other changes in clinical parameters or safety issues. Conclusions PAH therapies are used in adult patients with Fontan circulation followed in specialist centers, targeting individuals with advanced disease or complications. Follow-up suggests stabilization of the clinical status after 12 months of therapy.

Predicting Survival in Repaired Tetralogy of Fallot: A Lesion-Specific and Personalized Approach.

OBJECTIVES: This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA). BACKGROUND: To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF. METHODS: Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers. RESULTS: The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V02) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value. CONCLUSIONS: We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy.

AHA/ACC vs ESC Guidelines for Management of Adults With Congenital Heart Disease: JACC Guideline Comparison.

The American Heart Association and American College of Cardiology published practice guidelines for the management of adult congenital heart disease in 2018 and the European Society of Cardiology published analogous guidelines in 2020. Although there are broad areas of consensus between the 2 documents, there are important differences that impact patient management. This review discusses key areas of agreement and disagreement between the 2 guidelines, with discussion of possible reasons for disagreement and potential implications.

Enhanced Assessment of Perioperative Mortality Risk in Adults With Congenital Heart Disease.

BACKGROUND: In-hospital mortality is a rare, yet feared complication following cardiac surgery in adult congenital heart disease (ACHD). A risk score, developed and validated in ACHD, can be helpful to optimize risk assessment. OBJECTIVES: The purpose of this study was to assess the performance of EuroSCORE II components and procedure-related Adult Congenital Heart Surgery (ACHS) score, identify additional risk factors, and develop a novel risk score for predicting in-hospital mortality after ACHD surgery. METHODS: We assessed perioperative survival in patients aged >16 years undergoing congenital heart surgery in a large tertiary center between 2003 and 2019. A risk variable-derived PEACH (PErioperative ACHd) score was calculated for each patient. Internal and external validation of the model was undertaken, including testing in a validation cohort of patients operated in a second European ACHD center. RESULTS: The development cohort comprised 1,782 procedures performed during the study period. Re-sternotomy was undertaken in 897 (50.3%). There were 31 (1.7%) in-hospital deaths. The PEACH score showed excellent discrimination ability (area under the curve [AUC]: 0.88; 95% CI: 0.83-0.94), and performed better than the ACHS score in our population (ACHS AUC: 0.69; 95% CI: 0.6-0.78; P = 0.0003). A simple 3-tiered risk stratification was formed: PEACH score 0 (in-hospital mortality 0.2%), 1-2 (3.6%), and ≥3 (17.2%). In a validation cohort of 975 procedures, the PEACH score retained its discriminative ability (AUC: 0.75; 95% CI: 0.72-0.77) and was well calibrated (Hosmer-Lemeshow chi-square goodness-of-fit P = 0.55). There was agreement in expected and observed perioperative mortality between cohorts. CONCLUSIONS: The PEACH score is a simple, novel perioperative risk score developed and validated specifically for ACHD patients undergoing cardiac surgery.

When in Trouble Think of the Bubble: Paradoxical Cerebral Arterial Gas Embolism after Endoscopic Retrograde Cholangiopancreatography.

Air embolism (a result of direct communication with the vasculature and an external pressure gradient from the gastrointestinal or the biliary tract), although rare, is a potentially devastating adverse event seen in endoscopic retrograde cholangiopancreatography (ERCP) procedures. Whether venous, arterial, or paradoxical, the clinical presentation ranges from asymptomatic patients to cardiorespiratory arrest. This is of particular importance because it makes the diagnosis of air embolism even more difficult in an already sedated patient. Since early recognition increases the chances of patients' survival, endoscopists should be highly motivated and trained to recognize this complication as early as possible. With only 60 cases of air embolism reported (and even fewer related to paradoxical air embolism), we aimed to report a case of paradoxical cerebral air embolism in a patient undergoing ERCP due to a common bile duct stricture and to provide a mini-review of this clinical entity that can serve as a bedside quick reference guide for endoscopists worldwide.

Ultra-Fast-Track Extubation in Adult Congenital Heart Surgery.

Background In pediatric cardiac surgery, perioperative management has evolved from slow weaning of mechanical ventilation in the intensive care unit to "ultra-fast-track" anesthesia with early extubation (EE) in theater to promote a faster recovery. The strategy of EE has not been assessed in adults with congenital heart disease, a growing population of patients who often require surgery. Methods And Results Data were collected retrospectively on all patients >16 years of age who underwent adult congenital heart surgery in our tertiary center between December 2012 and January 2020. Coarsened exact matching was performed for relevant baseline variables. Overall, 711 procedures were performed: 133 (18.7%) patients underwent EE and 578 (81.3%) patients received conventional extubation. After matching, patients who received EE required less inotropic or vasopressor support in the early postoperative period (median Vasoactive-inotropic score 0.5 [0.0-2.0] versus 2.0 [0.0-3.5]; P<0.0001) and had a lower total net fluid balance than patients after conventional extubation (1168±723 versus 847±733 mL; P=0.0002). The overall reintubation rate was low at 0.3%. EE was associated with a significantly shorter postoperative length of stay in higher dependency care units before a "step-down" to ward-based care (48 [45-50] versus 50 [47-69] hours; P=0.004). Lower combined intensive care unit and high dependency unit costs were incurred by patients who received EE compared with patients who received conventional extubation (£3949 [3430-4222] versus £4166 [3893-5603]; P<0.0001). Conclusions In adult patients undergoing surgery for congenital heart disease, EE is associated with a reduced need for postoperative hemodynamic support, a shorter intensive care unit stay, and lower health-care-related costs.

Emergency department management of patients with adult congenital heart disease: a consensus paper from the ESC Working Group on Adult Congenital Heart Disease, the European Society for Emergency Medicine (EUSEM), the European Association for Cardio-Thoracic Surgery (EACTS), and the Association for Acute Cardiovascular Care (ACVC).

Adult congenital heart disease (ACHD) patients represent a growing population with increasing use of acute emergency department (ED) care. Providing comprehensive ED care necessitates an understanding of the most common clinical scenarios to improve morbidity and mortality in this population. The aim of this position document is to provide a consensus regarding the management of the most common clinical scenarios of ACHD patients presenting to the ED.

Palliative care in pulmonary hypertension associated with congenital heart disease: systematic review and expert opinion.

AIMS: Pulmonary arterial hypertension (PAH) is common amongst patients with congenital heart disease (CHD). It is a severe and complex condition that adversely affects quality of life and prognosis. While quality of life questionnaires are routinely used in clinical pulmonary hypertension practice, little is known on how to interpret their results and manage PAH-CHD patients with evidence of impaired health-related quality of life, especially those with advanced disease and palliative care needs. METHODS AND RESULTS: We performed a systematic review of studies concerning palliative care for people with PAH-CHD, also reviewing the health-related quality of life literature pertaining to these patients. Of 330 papers identified through initial screening, 17 were selected for inclusion. Underutilization of advance care planning and palliative care resources was common. Where palliative care input was sought, this was frequently late in the course of the disease. No studies provided evidence-based clinical criteria for triggering referral to palliative care, a framework for providing tailored care in this patient group, or how to manage the risk of sudden cardiac death and implantable cardioverter defibrillators in advanced PAH-CHD. We synthesize this information into eight important areas, including the impact of PAH-CHD on quality of life, barriers to and benefits of palliative care involvement, advance care planning discussions, and end-of-life care issues in this complex patient group, and provide expert consensus on best practice in this field. CONCLUSIONS: This paper presents the results of a systematic review and expert statements on the preferred palliative care strategy for patients with PAH-CHD.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells.

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance.

Prediction Models and Scores in Adult Congenital Heart Disease.

Nowadays, most patients with congenital heart disease survive to adulthood due to advances in pediatric cardiac surgery but often present with various comorbidities and long-term complications, posing challenges in their management. The development and clinical use of risk scores for the prediction of morbidity and/or mortality in adults with congenital heart disease (ACHD) is fundamental in achieving optimal management for these patients, including appropriate follow-up frequency, treatment escalation, and timely referral for invasive procedures or heart transplantation. In comparison with other fields of cardiovascular medicine, there are relatively few studies that report prediction models developed in the ACHD population, given the small sample size, heterogeneity of the population, and relatively low event rate. Some studies report risk scores originally developed in pediatric congenital or non-congenital population, externally validated in ACHD with variable success. Available risk scores are designed to predict heart failure or arrhythmic events, all-cause mortality, post-intervention outcomes, infective endocarditis, or atherosclerosis-related cardiovascular disease in ACHD. A substantial number of these scores are derived from retrospective studies and are not internally or externally validated. Adequately validated risk scores can be invaluable in clinical practice and an important step towards personalized medicine. Multicenter collaboration, adequate study design, and the potential use of artificial intelligence are important elements in the effort to develop reliable risk scores for the ACHD population.