Preoperative level of neutrophil-lymphocyte ratio: Comparison between cyanotic and acyanotic congenital heart disease.

INTRODUCTION: Elevated neutrophil-lymphocyte ratio (NLR) has been associated with poorer outcomes in children undergoing congenital heart surgery under cardiopulmonary bypass (CPB). OBJECTIVE: To compare preoperative NLR levels between cyanotic and acyanotic children undergoing surgical repair with CPB. METHODS: We performed a retrospective cohort study in 60-paired children (30 with tetralogy of Fallot [TOF] and 30 with ventricular septal defect [VSD]) between January 2018 and December 2019 matched by age, weight, and gender. Preoperative NLR was measured from the last complete blood count test before the surgery. All of them had negative viral screening. RESULTS: The median age in VSD children was 9.5 months (interquartile range [IQR]: 5-12), weight 7 kg (IQR: 5.5-8.7), 19 (63%) was female, and NLR was 0.45 (IQR: 0.3-0.65). The median age in TOF children was 8.5 months (IQR: 5-12), weight 7.6 kg (IQR: 5.8-8.7), 16 (53%) were female, and NLR was 0.67 (IQR: 0.41-1.1). Demographic parameters did not show any statistically significant difference between groups (p > .05). Children with TOF had higher preoperative NLR compared with VSD patients (p = .004). As lower O2 saturation as higher the NLR (p = .005). CONCLUSION: The preoperative level of NLR was higher in cyanotic congenital heart disease patients.

The role of the neutrophil-lymphocyte ratio for pre-operative risk stratification of acute kidney injury after tetralogy of Fallot repair.

INTRODUCTION: Acute kidney injury is a risk factor for chronic kidney disease and mortality after congenital heart surgery under cardiopulmonary bypass. The neutrophil-lymphocyte ratio is an inexpensive and easy to measure biomarker for predicting outcomes in children with congenital heart disease undergoing surgical correction. OBJECTIVE: To identify children at high risk of acute kidney injury after tetralogy of Fallot repair using the neutrophil-lymphocyte ratio. METHODS: This single-centre retrospective analysis included consecutive patients aged < 18 years who underwent tetralogy of Fallot repair between January 2014 and December 2018. The pre-operative neutrophil-lymphocyte ratio was measured using the last pre-operative complete blood count test. We used the Acute Kidney Injury Network definition. RESULTS: A total of 116 patients were included, of whom 39 (33.6%) presented with acute kidney injury: 20 (51.3%) had grade I acute kidney injury, nine had grade II acute kidney injury (23.1%), and 10 (25.6%) had grade III acute kidney injury. A high pre-operative neutrophil-lymphocyte ratio was associated with grade III acute kidney injury in the post-operative period (p = 0.04). Patients with acute kidney injury had longer mechanical ventilation time (p = 0.023), intensive care unit stay (p < 0.001), and hospital length of stay (p = 0.002). CONCLUSION: Our results suggest that the pre-operative neutrophil-lymphocyte ratio can be used to identify patients at risk of developing grade III acute kidney injury after tetralogy of Fallot repair.

Y-shaped Bifurcated Graft to Pulmonary Arteries After Arterial Switch Operation.

Pulmonary artery stenosis is a frequent complication after arterial switch operation. This case study presented a complex pulmonary artery stenosis initially treated with bilateral pulmonary artery stenting. The patient was found to have aortic valve endocarditis and recurrent pulmonary artery stenosis. The aortic valve was replaced and the pulmonary valve was repaired, followed by interposition of a Y-shaped graft from the sinotubular junction to both pulmonary arteries. The patient had an uneventful recovery and was discharged home asymptomatic after endocarditis antibacterial treatment.

Mucopolysaccharidosis type VI: case report with first neonatal presentation with ascites fetalis and rapidly progressive cardiac manifestation.

BACKGROUND: The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease. CASE PRESENTATION: A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age. CONCLUSIONS: We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.

Multimodality Screening of Hepatic Nodules in Patients With Congenital Heart Disease After Fontan Procedure: Role of Ultrasound, ARFI Elastography, CT, and MRI.

OBJECTIVE: Currently, there is no consensus in the literature regarding the screening of hepatic nodules in patients who have undergone the Fontan procedure. The objectives of this study are to evaluate in this population the frequency of hepatic nodules at ultrasound (US), CT, and MRI; to measure liver stiffness using acoustic radiation force impulse (ARFI) elastography; and to investigate predictive factors for hepatic nodules. SUBJECTS AND METHODS: In this cross-sectional study, 49 patients who underwent the Fontan procedure were prospectively recruited from August 2014 through June 2016. These patients underwent clinical evaluation for hepatic disorders, ARFI elastography, US, CT, and MRI. RESULTS: Most of the patients had no symptoms, and hepatic nodules were detected in three of 49 (6.1%) patients at US, 14 of 44 (31.8%) patients at CT, and 19 of 48 (39.6%) patients at MRI. Liver stiffness at ARFI elastography was significantly higher in patients with hepatic nodules than in patients without such nodules (2.64 ± 0.81 m/s vs 1.94 ± 0.49 m/s; p = 0.002) and was a significant predictor of hepatic nodule (AUC, 0.767; p = 0.002). No clinical or laboratory data had any significant correlation with the existence of hepatic nodules, including time since Fontan procedure. CONCLUSION: In our study, more than one-third of patients had hepatic nodules at CT or MRI, but US did not detect most hepatic nodules. Liver stiffness at ARFI elastography was significantly higher in patients with hepatic nodules, and it may help guiding which patient should be further imaged with CT or MRI.

Familial Profile of Pediatric and Adult Patients With Congenital Heart Disease in Heart Transplantation.

Congenital heart disease is the most common birth defect, and heart transplantation is the main treatment of choice. As genetic causes can be identified in a considerable proportion of cases, investigation of possible family cardiac history is essential. We analyzed the profiles of pediatric heart transplant recipients in terms of family history of heart disease. This single-center retrospective study included pediatric patients who underwent heart transplantation at a tertiary hospital between 2013 and 2023. Out of 170 patients, 13 had a family history relevant to congenital heart disease, with an emphasis on the etiology of dilated cardiomyopathy and the occurrence of the same heart disease in siblings. These results can impact the management of patients with congenital heart disease.

Predictors of in-ICU length of stay among congenital heart defect patients using artificial intelligence model: A pilot study.

Objective: This study aims to develop a predictive model using artificial intelligence to estimate the ICU length of stay (LOS) for Congenital Heart Defects (CHD) patients after surgery, improving care planning and resource management. Design: We analyze clinical data from 2240 CHD surgery patients to create and validate the predictive model. Twenty AI models are developed and evaluated for accuracy and reliability. Setting: The study is conducted in a Brazilian hospital's Cardiovascular Surgery Department, focusing on transplants and cardiopulmonary surgeries. Participants: Retrospective analysis is conducted on data from 2240 consecutive CHD patients undergoing surgery. Interventions: Ninety-three pre and intraoperative variables are used as ICU LOS predictors. Measurements and main results: Utilizing regression and clustering methodologies for ICU LOS (ICU Length of Stay) estimation, the Light Gradient Boosting Machine, using regression, achieved a Mean Squared Error (MSE) of 15.4, 11.8, and 15.2 days for training, testing, and unseen data. Key predictors included metrics such as "Mechanical Ventilation Duration", "Weight on Surgery Date", and "Vasoactive-Inotropic Score". Meanwhile, the clustering model, Cat Boost Classifier, attained an accuracy of 0.6917 and AUC of 0.8559 with similar key predictors. Conclusions: Patients with higher ventilation times, vasoactive-inotropic scores, anoxia time, cardiopulmonary bypass time, and lower weight, height, BMI, age, hematocrit, and presurgical oxygen saturation have longer ICU stays, aligning with existing literature.

Myocardial tissue expression of mRNA and preoperative neutrophil-lymphocyte ratio in children undergoing congenital heart surgery.

Background: The neutrophil-lymphocyte ratio (NLR) is an easily accessible and inexpensive biomarker that has been shown to predict morbidity and mortality in congenital cardiac surgery. However, its regulatory mechanism remains unclear. This study aims to compare and correlate the tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10 messenger RNAs (mRNAs) with the NLR in patients with tetralogy of Fallot (ToF) and ventricular septal defect (VSD). Methods: A prospective translational study was conducted on 10 children with ToF and 10 with VSD, aged between 1 and 24 months. The NLR was calculated from the blood count taken 24 hours before surgery. The expression of these mRNAs was analyzed in the myocardial tissue of the right atrium prior to cardiopulmonary bypass. Results: Patients with ToF exhibited a higher NLR [ToF 0.46 (interquartile range; IQR) 0.90; VSD 0.28 (IQR 0.17); P=0.02], longer mechanical ventilation time [ToF 24 h (IQR 93); VSD 5.5 h (IQR 8); P<0.001], increased use of vasoactive drugs [ToF 2 days (IQR 1.75); VSD 0 (IQR 1); P=0.01], and longer ICU [ToF 5.5 (IQR 1); VSD 2 (IQR 0.75); P=0.02] and hospital length of stays [ToF 18 days (IQR 17.5); VSD 8.5 days (IQR 2.5); P<0.001]. A negative correlation was found between NLR and oxygen saturation (SaO2) (r=-0.44; P=0.002). In terms of mRNA expression, the ToF group showed a lower expression of IL-10 mRNA (P=0.03). A positive correlation was observed between IL-10-mRNA and SaO2 (r=0.40; P=0.07), and a negative correlation with NLR (r=-0.27; P=0.14). Conclusions: Patients with ToF demonstrated a higher preoperative NLR and lower IL-10 mRNA expression by what appears to be a pro-inflammatory phenotype of cyanotic patients.

Challenges of Congenital Heart Surgery in Brazil: It is Time to Designate Pediatric Congenital Heart Surgery Subspecialty.

Congenital heart disease (CHD) affects eight to ten out of every 1,000 births, resulting in approximately 23,057 new cases in Brazil in 2022. About one in four children with CHD requires surgery or other procedures in the first year of life, and it is expected that approximately 81% of these children with CHD will survive until at least 35 years of age. Professionals choosing to specialize in CHD surgery face numerous challenges, not only related to mastering surgical techniques and the complexity of the diseases but also to the lack of recognition by medical societies as a separate subspecialty. Furthermore, families face difficulties when access to services capable of providing treatment for these children. To address these challenges, it is essential to have specialized hospitals, qualified professionals, updated technologies, sustainable industry, appropriate financing, quality assessment systems, and knowledge generation. The path to excellence involves specialization across all involved parties. As we reflect on the importance of Pediatric Cardiovascular Surgery and Congenital Heart Diseases establishing themselves as a subspecialty of Cardiovascular Surgery, it is essential to look beyond our borders to countries like the United States of America and United Kingdom, where this evolution is already a reality. This autonomy has led to significant advancements in research, education, and patient care outcomes, establishing a care model. By following this path in Brazil, we not only align our practice with the highest international standards but also demonstrate our maturity and the ability to meet the specific needs of patients with CHD and those with acquired childhood heart disease.

Case Report: The Challenge for Diagnosis of Myocarditis and Transplant Rejection After COVID Infection in a Heart-Transplanted Adolescent.

Patients who have undergone organ transplantation are immunosuppressed hosts, leaving them at a higher risk of infections. SARS-COV-2 has been shown to affect heart-transplanted patients. In this case report, we present the case of a 14-year-old heart transplant recipient who developed signs and symptoms of heart failure, along with fatigue, after a COVID-19 infection. An endomyocardial biopsy was performed to diagnose rejection and to evaluate whether this was myocarditis due to SARS-COV-2. The biopsy showed intense acute cellular rejection (3R) and antibody rejection PAMR1 H+ but was negative for the SARS-CoV-2 virus. The patient received organ rejection therapy with high-dose methylprednisolone and human immunoglobulin. After treatment, her heart function recovered, with biopsy investigations showing a lower level of cellular rejection (1R).

Heart Transplantation in Children and Adults With Congenital Heart Disease: 3 Decades of Evolution.

Heart transplantation is the treatment of choice for children and adults with congenital heart disease. We report the heart transplant single-center experience. The number of transplantations has increased over the last 3 decades. The Kaplan-Meier survival curves in the first, second, and third decades at 5 and 10 years were 69% and 59%, 62% and 52%, and 66% and 60%, respectively.

Mechanical Circulatory Assistance in Children: Clinical Outcome.

BACKGROUND: In countries where organ donation is scarce, mortality in the pediatric heart transplant waiting list is high, and ventricular assist devices (VADs) are therapeutic alternatives in these situations. Berlin Heart EXCOR is currently 1 of the few VADs specific for children. METHODS: This retrospective study includes pediatric patients who underwent Berlin Heart EXCOR placement in a Brazilian hospital between 2012 and 2021. Clinical and laboratory data at the time of VAD implantation and the occurrence of complications and outcomes (success as a bridge to transplant or death) were analyzed. RESULTS: Eight patients, from 8 months to 15 years, were included: 6 with cardiomyopathy and 2 with congenital heart disease. Six were on Intermacs 1 and 2 on Intermacs 2. The most common complications observed were stroke and right ventricular dysfunction. Six were transplanted, and 2 died. Those submitted to transplant had a higher mean weight than those who died, with no statistically significant difference. The underlying disease had no impact on the outcome. The group undergoing transplant had lower brain natriuretic peptide and lactate values, but no laboratory variable showed a statistically significant difference in the outcome. CONCLUSION: A VAD is an invasive treatment with potentially serious adverse effects and is still poorly available in Brazil. However, as a bridge to transplant, it is a useful treatment for children in progressive clinical decline. In this study, we did not observe any clinical or laboratory factor at the time of VAD implantation that implied better outcomes.

Performance Evaluation of Geometrically Different Pediatric Arterial Cannulae in a Pediatric Cardiopulmonary Bypass Model.

OBJECTIVE: To define a reference chart comparing pressure drop vs. flow generated by a set of arterial cannulae currently utilized in cardiopulmonary bypass conditions in pediatric surgery. METHODS: Cannulae from two manufacturers were selected considering their design and outer and inner diameters. Cannula performance was evaluated in terms of pressure drop vs. flow during simulated cardiopulmonary bypass conditions. The experimental circuits consisted of a Jostra HL-20 roller pump, a Quadrox-i pediatric oxygenator (Maquet Cardiopulmonary AG, Rastatt, Germany), and a custom pediatric tubing set. The circuit was primed with lactated Ringer's solution only (first condition) and with human packed red blood cells added (second condition) to achieve a hematocrit of 30%. Cannula sizes 8 to 16 Fr were inserted into the cardiopulmonary bypass circuit with a "Y" connector. The flow was adjusted in 100 ml/min increments within typical flow ranges for each cannula. Pre-cannula and post-cannula pressures were measured to calculate the pressure drop. RESULTS: Utilizing a pressure drop limit of 100 mmHg, our results suggest a recommended flow limit of 500, 900, 1400, 2600, and 3100 mL/min for Braile arterial cannulae sizes 8, 10, 12, 14, and 16 Fr, respectively. For Medtronic DLP arterial cannulae sizes 8, 10, 12, 14, and 16 Fr, the recommended flow limit is 600, 1100, 1700, 2700, and 3300 mL/min, respectively. CONCLUSION: This study reinforces discrepancies in pressure drop between cannulae of the same diameter supplied by different manufacturers and the importance of independent translational research to evaluate components' performance.

Desmoid tumour of the chest wall in paediatric post-operatory of heart transplant.

We will report a case of a desmoid tumour (DT), which developed at the surgical site of the pacemaker after a late childhood heart transplant. Patients with idiopathic dilated cardiomyopathy followed up in the paediatric cardiology service. It evolved with the dissociation of ventricular rhythm caused by severe heart failure, which led to the implantation of a cardiac resynchronization device prior to heart transplantation. The progression to end-stage heart disease culminated in a heart transplant at 12 years old. One year after the transplant, at the age of 13 years, he presented a progressively growing mass on the generator site of the resynchronization device. The initial decision was to remove the device. During the removal surgery, there was no haematoma or fluid collection. However, there was a progression of the lesion. The lesion was biopsied with the anatomopathological diagnosis of a DT. Resection surgery happened 4 months after the start of the mass growth. At that time, the tumour reached 20 cm in diameter. The lesion infiltrated the pectoralis major muscle and this muscle was resected partially en bloc with the lesion. The defect had primary closure. The patient evolved without postoperative complications and was discharged on the 14th postoperative day. The surgical specimen came with negative circumferential margins. However, the deep margin was microscopically positive. Due to deep involvement, the patient underwent adjuvant radiotherapy. Currently, the patient is under clinical follow-up and has no evidence of tumour recurrence. DT is a rare tumour, with unpredictable courses. Surgery can be considered in the progression of lesions. Treatment is justified by long survival after a heart transplant and in DT patients. DT is a differential diagnosis to be considered in progressive growth lesions.

Surgical Correction of Ascending Aortic Aneurysm Without Coronary Dilatation After Kawasaki Disease in a 3-Year-Old Child.

Kawasaki disease (KD) is an inflammatory condition that may affect genetically predisposed individuals in pediatric ages after infectious/environmental triggering. An infrequent finding associated with KD is ascending aortic aneurysm during or after the acute phase of the disease. In this Multimedia presentation, we describe a three-year-old girl submitted to surgical treatment.

Early Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review.

Background and Aims: Congenital heart diseases (CHDs) are diagnosed in approximately 9 in 1,000 newborns, and early cardiac corrective surgery often requires partial or complete thymectomy. As the long-term effect of early thymectomy on the subsequent development of the immune system in humans has not been completely elucidated, the present study aimed to evaluate the effects of thymus removal on the functional capacity of the immune system after different periods. Methods: A systematic review of the literature was performed using MEDLINE, EMBASE, LILACS and Scopus. The inclusion criteria were original studies that analyzed any component of the immune system in patients with CHD who had undergone thymectomy during cardiac surgery in the first years of life. The results were evaluated for the quality of evidence. Results: Twenty-three studies were selected and showed that patients who underwent a thymectomy in the first years of life tended to exhibit important alterations in the T cell compartment, such as fewer total T cells, CD4+, CD8+, naïve and CD31+ T cells, lower TRECs, decreased diversity of the TCR repertoire and higher peripheral proliferation (increased Ki-67 expression) than controls. However, the numbers of memory T cells and Treg cells differed across the selected studies. Conclusions: Early thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland. Systematic Review Registration: Prospero [157188].

Functional lymphatic reserve capacity is depressed in patients with a Fontan circulation.

BACKGROUND: Lymphatic abnormalities play a role in effusions in individuals with a Fontan circulation. Recent results using near-infrared fluorescence imaging disclosed an increased contraction frequency of lymphatic vessels in Fontan patients compared to healthy controls. It is proposed that the elevated lymphatic pumping seen in the Fontan patients is necessary to maintain habitual interstitial fluid balance. Hyperthermia has previously been used as a tool for lymphatic stress test. By increasing fluid filtration in the capillary bed, the lymphatic workload and contraction frequency are increased accordingly. Using near-infrared fluorescence imaging, the lymphatic functional reserve capacity in Fontan patients were explored with a lymphatic stress test. METHODS: Fontan patients (n = 33) were compared to a group of 15 healthy individuals of equal age, weight, and gender. The function of the superficial lymphatic vessels in the lower leg during rest and after inducing hyperthermia was investigated, using near-infrared fluorescence imaging. RESULTS: Baseline values in the Fontan patients showed a 57% higher contraction frequency compared to the healthy controls (0.4 ± 0.3 min-1 vs. 0.3 ± 0.2 min-1 , p = 0.0445). After inducing stress on the lymphatic vessels with hyperthermia the ability to increase contraction frequency was decreased in the Fontan patients compared to the controls (0.6 ± 0.5 min-1 vs. 1.2 ± 0.8 min-1 , p = 0.0102). CONCLUSIONS: Fontan patients had a higher lymphatic contraction frequency during normal circumstances. In the Fontan patients, the hyperthermia response is dampened indicating that the functional lymphatic reserve capacity is depressed. This diminished reserve capacity could be part of the explanation as to why some Fontan patients develop late-onset lymphatic complications.

Preoperative Neutrophil-Lymphocyte Ratio Can Predict Outcomes for Patients Undergoing Tetralogy of Fallot Repair.

INTRODUCTION: Elevated neutrophil-lymphocyte ratio (NLR) has been associated with poorer outcomes in cyanotic patients undergoing single ventricle palliation. Little is known about this biomarker on patients with tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. Our objective is to study the impact of preoperative NLR on outcomes of TOF patients undergoing total repair. METHODS: This retrospective study included 116 consecutive patients between January 2014 and December 2018. Preoperative NLR was measured from the last complete blood count test before the surgery. Using the cutoff value of 0.80, according to the receiver-operating characteristic (ROC) curve, the sample was divided into two groups (NLR < 0.80 and ≥ 0.80). The primary endpoint was hospital length of stay (LOS). RESULTS: ROC curves showed that higher preoperative NLR was associated with longer hospital LOS, with an area under the curve of 0.801±0.040 (95% confidence interval 0.722 - 0.879; P<0.001). High preoperative NLR was also associated with long intensive care unit (ICU) LOS (P=0.035). Preoperative NLR predicted longer hospital LOS with a sensitivity of 63% and a specificity of 81.4%. CONCLUSION: Higher preoperative NLR was associated with long ICU and hospital LOS in patients undergoing TOF repair.

Impact of COVID-19 Pandemic in a Pediatric and Congenital Cardiovascular Surgery Program in Brazil.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has negatively impacted healthcare services worldwide. We hypothesized that the pandemic would affect our case mix and mortality. Our objective was to study this impact. METHODS: We retrospectively studied all patients who underwent congenital heart surgeries from March 21st to August 21st in 2019 and 2020 using the institutional electronic database. We compared demographic data, preoperative and postoperative length of stay (LOS), risk stratification using Risk Adjustment for Congenital Heart Surgery (RACHS) classification and outcomes in both periods. RESULTS: We observed a 66.7% decrease in our surgical volume (285 × 95 patients). Patients operated in the pre-pandemic period were older (911.3 [174.8 - 5953.8] days-old) compared to the pandemic period (275 days-old; P<0.05). When the case mix was compared between periods, the percentage of neonatal surgery was increased in the pandemic era (8% × 21.1%; P<0.05), and the number of RACHS 1-2 surgeries decreased significantly (60.7 × 27.4%; P<0.05). Preoperative LOS was increased in the pandemic period (1.2 × 7 days; P=0.001). There was no significant increment in mortality (P=0.1). Two patients tested positive for COVID-19 in the postoperative period and both died. CONCLUSION: Our program observed a sudden decrease in surgical volume and a consequent increase in surgical complexity. There was a non-significant increment in mortality.