Turner syndrome may be associated with hepatic adenoma.

Turner syndrome, caused by complete or partial loss of an X chromosome, is marked by a range of clinical manifestations including short stature, cardiovascular and renal disease. Hepatic involvement is an increasingly recognized concern. Steatosis and elevated transaminases are commonly observed in this population, but case reports have also described hepatic adenoma. Hepatic adenomas are rare, occurring in one per million people in the general population. They are typically benign but malignant transformation or rupture can occur. We sought to investigate whether Turner syndrome is associated with hepatic adenoma. Patients with Turner syndrome encountered at a single, academic institution between 2006 and 2020 were identified using ICD-10 codes and demographic, medication, laboratory, and imaging data were analyzed. Of the 228 patients identified, 46.9% had liver function testing, which were abnormal in 48.6%. Five of 77 patients with hepatic imaging had abnormalities. Three patients (1.3%) had hepatic adenoma, one after presenting in hemorrhagic shock due to rupture. These findings suggest that patients with Turner syndrome may have an increased risk for developing hepatic adenoma. Annual monitoring of liver function tests is already recommended in Turner syndrome. The addition of periodic hepatic imaging may also be beneficial.

COVID-19-Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease.

Background: Altered coagulation is a striking feature of COVID-19. Adult patients with congenital heart disease (ACHD) are prone to thromboembolic (TE) and bleeding complications. Objectives: The purpose of this study was to investigate the prevalence and risk factors for COVID-19 TE/bleeding complications in ACHD patients. Methods: COVID-19-positive ACHD patients were included between May 2020 and November 2021. TE events included ischemic cerebrovascular accident, systemic and pulmonary embolism, deep venous thrombosis, myocardial infarction, and intracardiac thrombosis. Major bleeding included cases with hemoglobin drop >2 g/dl, involvement of critical sites, or fatal bleeding. Severe infection was defined as need for intensive care unit, endotracheal intubation, renal replacement therapy, extracorporeal membrane oxygenation, or death. Patients with TE/bleeding were compared to those without events. Factors associated with TE/bleeding were determined using logistic regression. Results: Of 1,988 patients (age 32 [IQR: 25-42] years, 47% male, 59 ACHD centers), 30 (1.5%) had significant TE/bleeding: 12 TE events, 12 major bleeds, and 6 with both TE and bleeding. Patients with TE/bleeding had higher in-hospital mortality compared to the remainder cohort (33% vs 1.7%; P < 0.0001) and were in more advanced physiological stage (P = 0.032) and NYHA functional class (P = 0.01), had lower baseline oxygen saturation (P = 0.0001), and more frequently had a history of atrial arrhythmia (P < 0.0001), previous hospitalization for heart failure (P < 0.0007), and were more likely hospitalized for COVID-19 (P < 0.0001). By multivariable logistic regression, prior anticoagulation (OR: 4.92; 95% CI: 2-11.76; P = 0.0003), cardiac injury (OR: 5.34; 95% CI: 1.98-14.76; P = 0.0009), and severe COVID-19 (OR: 17.39; 95% CI: 6.67-45.32; P < 0.0001) were independently associated with increased risk of TE/bleeding complications. Conclusions: ACHD patients with TE/bleeding during COVID-19 infection have a higher in-hospital mortality from the illness. Risk of coagulation disorders is related to severe COVID-19, cardiac injury during infection, and use of anticoagulants.

Optimizing efficiency of a custom clinical decision support tool improves adult congenital heart disease care.

Study objective: Improve the efficiency of an inpatient clinical decision support tool (CDS) for patients with adult congenital heart disease (ACHD). Design: The efficiency of a CDS was evaluated across two time periods and compared. Setting: An academic, tertiary care center. Participants: ACHD patients roomed in an inpatient setting. Intervention: Plan-Do-Study-Act (PDSA) methods were applied starting in 2021 and included refinement of diagnostic codes and the addition of department encounter codes. Main outcome measures: True positive and false positive CDS alerts. Results: Baseline data from 2017 had a median (IQR) of 38 (17) and 2019 baseline data had 65 (19) total alerts per month. Combining both baseline data years, the median true positive CDS alerts was 47.3 %. There were 71 (6) total alerts per month for the 2021-2022 time period and with ongoing PDSA cycles and optimization in the CDS the true positive alerts improved substantially resulting in a shifting of the median to 78.9 % within 9 months. Conclusion: CDS can efficiently notify providers when an ACHD patient is encountered. The use of ICD 10 codes alone to identify ACHD patients has limited accuracy with a high proportion of false positives. Ongoing revision of the CDS system methods is important to improving efficiency and minimizing provider alert fatigue.

New-Onset Accelerated Idioventricular Rhythm During Dental Rehabilitation.

Accelerated idioventricular rhythm has been documented in several cases involving the induction of general anesthesia; however, it has not previously been known to occur during reversal of neuromuscular blockade with neostigmine and glycopyrrolate. The current understanding of the pathophysiology of accelerated idioventricular rhythm involves enhanced automaticity of ventricular myocardium in the setting of increased vagal tone suppressing sinoatrial node pace making. We present the case of an 8-year-old boy who developed accelerated idioventricular rhythm during dental rehabilitation. In this case, accelerated idioventricular rhythm developed immediately upon reversal of neuromuscular blockade with neostigmine and glycopyrrolate and recurred intermittently during his recovery in the postanesthesia care unit. This was a benign occurrence in our patient who remained asymptomatic and hemodynamically stable, and his arrhythmia eventually subsided without intervention after several hours of telemetry. This case suggests that reversal of neuromuscular blockade with neostigmine and glycopyrrolate may induce accelerated idioventricular rhythm in certain patients without known cardiovascular disease.

Impact of the COVID-19 pandemic on cardiometabolic health parameters in children with preexisting dyslipidemia.

BACKGROUND: The COVID-19 pandemic has raised concerns for worsening cardiometabolic health in children. OBJECTIVE: This study evaluates the impact of the COVID-19 pandemic and subsequent social restrictions on pediatric cardiometabolic health factors. METHODS: Retrospective review of patients in a pediatric lipid clinic in the year prior to (3/18/2019-3/17/2020) and during (3/18/2020-3/17/2021) the COVID-19 pandemic was performed. Physical findings (body mass index [BMI], waist circumference [WC], and blood pressure), laboratory markers of cardiometabolic health (lipid panel, insulin resistance, and liver transaminases), self-reported exercise time, and lipid-lowering medications (metformin, statin, omega-3 fatty acids, fenofibrate) were compared. RESULTS: 297 subjects met inclusion criteria. Among subjects prescribed no medications or on stable medication doses (n=241), there were few changes in lipid panels. Among subjects with new or increased medication doses between pre-pandemic and pandemic intervals (n=62), there were increases in triglycerides (p= 0.019) and HgbA1c (p=0.046). There was no change in z-scores for both BMI and WC for either group. CONCLUSION: We observed concerning trends in markers of cardiovascular disease health (dyslipidemia, insulin resistance, and diabetes), independent of changes in weight, in at-risk children during the recent COVID pandemic. Our findings suggest that this vulnerable population may benefit from more frequent monitoring and intense management during such events.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Prevalence and Long-Term Outcomes of Solid Organ Transplant in Children with Intellectual Disability.

OBJECTIVES: To describe the prevalence and long-term outcomes of kidney, liver, and heart transplant for children with an intellectual disability. STUDY DESIGN: We performed a retrospective cohort analysis of children receiving a first kidney, liver, or heart-alone transplant in the United Network for Organ Sharing dataset from 2008 to 2017. Recipients with definite intellectual disability were compared with those possible/no intellectual disability. Kaplan-Meier survival estimates were calculated for graft and patient survival. Cox proportional hazard models were used to estimate the association between intellectual disability and graft and patient survival. RESULTS: Over the study period, children with definite intellectual disability accounted for 594 of 6747 (9%) first pediatric kidney-alone, 318 of 4566 (7%) first pediatric liver-alone, and 324 of 3722 (9%) first pediatric heart-alone transplant recipients. Intellectual disability was not significantly associated with patient or graft survival among liver and heart transplant recipients. Among kidney transplant recipients, definite intellectual disability was significantly associated with higher graft survival and lower patient survival, but the absolute differences were small. CONCLUSIONS: Children with intellectual disability account for 7%-9% of pediatric transplant recipients with comparable long-term outcomes to other pediatric recipients. These findings provide important empirical support for policies that include children with intellectual disability as transplant candidates.

Technical Performance Score Predicts Perioperative Outcomes in Complex Congenital Heart Surgery Performed in a Small-to-Medium-Volume Program.

As the quality of surgical outcomes depend on many factors, the development of validated tools to assess the different aspects of complex multidisciplinary teams' performance is crucial. The Technical Performance Score (TPS) has only been validated to correlate with outcomes in large-volume surgical programs. Here we assess the utility of TPS in correlation to perioperative outcomes for complex congenital heart surgeries (CHS) performed in a small-to-medium-volume program. 673 patients underwent CHS from 4/2012 to 12/2017 at our institution. Of those, 122 were STAT 4 and STAT 5. TPS was determined for each STAT 4 and STAT 5 operation using discharge echocardiogram: 1 = optimal, 2 = adequate, 3 = inadequate. Patient outcomes were compared including mortality, length of stay, ventilation times, and adverse events. 69 patients (57%) were neonates, 32 (26%) were infants, 17 (14%) were children, 4 (3%) were adults. TPS class 1 was assigned to 85 (70%) operations, TPS class 2 was assigned to 25 (20%) operations, and TPS class 3 was assigned to 12 (10%) operations. TPS was associated with re-intubation, ICU length of stay, postoperative length of stay, and mortality. TPS did not correlate with unplanned 30-day readmissions, need for reoperation, and inotropic score. Technical performance score was associated with perioperative outcomes and is a useful tool to assess the adequacy of repair for high complexity CHS in a small-to-medium-volume surgical program. TPS should be a part of program review in congenital heart programs of all sizes to identify strategies that may reduce postoperative morbidity and potentially improve long-term outcomes.

Sex-Specific Differences in Ventricular Dimensions in Repaired Tetralogy of Fallot: A Retrospective Study.

The timing of pulmonary valve replacement (PVR) in asymptomatic patients with repaired tetralogy of Fallot (TOF) is typically based on cardiac magnetic resonance imaging-derived ventricular volume measurements. Current criteria do not account for sex-based differences in chamber size. The purpose of this study was to compare male and female ventricular volumes and function in TOF patients with a hypothesis that females are less likely to meet common-indexed right ventricular end-diastolic volume (RVEDVi) and right ventricular end-systolic volume (RVESVi) criteria for PVR. Cardiac magnetic resonance data from 17 females (age 31.7 ± 15.4 years) and 23 males (30.7 ± 15.4 years) with TOF were retrospectively analyzed. Demographic and imaging data were recorded. Differences in sex-based means and standard deviations were evaluated using the Wilcoxon rank-sum test with continuity correction. Age and pulmonary regurgitant fraction were similar in females and males. RVEDVi was lower in females than in males, but the difference was not statistically significant. Differences in RVESVi, LVEDVi, LVESVi, and left ventricular ejection fraction were statistically significant, while the difference in right ventricular ejection fraction was not. RVEDVi was greater than 150 mL/m2 in 3/17 (17.6%) females and 10/23 (43.5%) males (OR 3.6). RVESVi was greater than 82 mL/m2 in 2/17 females and 8/23 males (OR 4.0). Sex-specific differences in right ventricular and left ventricular volumes and function are present in patients with TOF despite similar pulmonary regurgitation. These differences may need to be considered when evaluating patients for PVR.

Analysis of cavopulmonary and cardiac flow characteristics in fontan Patients: Comparison with healthy volunteers.

BACKGROUND: Characterizing the flow of the Fontan circuit, and correlating flow characteristics with the development of complications, is an important clinical challenge. Past work has analyzed the flow characteristics of Fontan circulation on a component-by-component basis. 4D flow MRI with radial projections allows for large volumetric coverage, and therefore can be used to analyze the flow through many codependent cardiovascular components in a single imaging session. PURPOSE: To describe flow characteristics across the entire Fontan circuit and to compare these with the flow characteristics in healthy volunteers. STUDY TYPE: Prospective. SUBJECTS: Eleven single ventricle patients with a Fontan connection and 15 healthy controls. SEQUENCE: Phase contrast with vastly undersampled isotropic projection reconstruction (PC-VIPR) at a field strength of 3 T. ASSESSMENT: Cavopulmonary and ventricular flow distributions, blood flow kinetic energy, vorticities, efficiency indices, and other flow parameters were analyzed using Ensight and MatLab. STATISTICAL TESTS: The results were compared across Fontan subjects, between respiratory phases, and between Fontan subjects and healthy volunteers using a Student's t-test for unequal sample sizes and linear regression. RESULTS: Cava-specific pulmonary flow distributions of Fontan patients varied significantly between respiratory phases (P < 0.05). Ventricular kinetic energy (KE) was significantly higher in Fontan patients than it was in healthy controls, leading to a lower cardiac efficiency metric in the Fontan group. A significant diastolic KE time-shift was also observed in the Fontan patient group. Peak diastolic KE was significantly higher in the single ventricle of patients with right ventricle morphology than it was in left ventricle morphology patients. DATA CONCLUSION: Radial 4D flow MRI can be used for comprehensive analysis of single ventricle Fontan flow characteristics. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019.

Geleophysic dysplasia: 48 year clinical update with emphasis on cardiac care.

Geleophysic dysplasia is a rare skeletal dysplasia often complicated by progressive cardiac disease. Information about long-term outcomes is limited. A clinical update of the oldest surviving patient described with geleophysic dysplasia type 1 is provided. Special note is made in relation to the cardiac disease and interventions. Genetic testing of ADAMTSL2 revealed a previously reported missense mutation as well as a novel nonsense mutation, which can be added to the list of causative mutations in geleophysic dysplasia.

Prevalence and outcomes of heart transplantation in children with intellectual disability.

Heart transplantation in children with intellectual disability is a controversial issue. We sought to describe the prevalence and outcomes of heart transplantation in children with intellectual disability and hypothesized that recipients with intellectual disability have comparable short-term outcomes compared to recipients without intellectual disability. We performed a retrospective cohort analysis of children receiving a first heart-alone transplant in the UNOS STAR database from 2008 to 2013. Recipients with intellectual disability were compared to those without using chi-square tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between intellectual disability and graft failure and patient survival. Over the study period, 107 children with intellectual disability underwent initial heart transplantation, accounting for 8.9% of first pediatric heart transplants (total=1204). There was no difference in the incidence of acute rejection between groups in the first year after transplant. Mean functional status scores at follow-up improved in both groups after transplantation, but tended to be lower among children with intellectual disability than children without. Log-rank tests did not suggest significant differences in graft survival between those with and without intellectual disability during the first 4 years following transplantation. Children with intellectual disability constitute a significant portion of total heart transplants with short-term outcomes comparable to children without intellectual disability.

Minimally Invasive Esophagectomy in a Patient With Tetralogy of Fallot and Right-Sided Aortic Arch.

Improvements in surgical technique and perioperative care have resulted in increased long-term survival for patients with congenital heart disease. As these patients begin to reach their later years, clinicians are challenged with determining optimal management of noncardiac diseases in this complex patient population, including surgically treatable malignancies. We present a case of esophageal cancer in a patient with previously repaired tetralogy of Fallot and right-sided aortic arch, treated with neoadjuvant therapy followed by laparoscopic and left thoracoscopic esophagectomy.

Neonatal Enterovirus Infection: Case Series of Clinical Sepsis and Positive Cerebrospinal Fluid Polymerase Chain Reaction Test with Myocarditis and Cerebral White Matter Injury Complications.

Objective We describe five neonates with enteroviral (EV) infection to demonstrate central nervous system (CNS) and cardiac complications and report successful treatment of myocarditis with immunoglobulin intravenous (IVIG) in two. Study Design Case series identified during three enteroviral seasons in one neonatal intensive care unit (NICU) by cerebral spinal fluid (CSF) reverse transcriptase polymerase chain reaction (PCR) testing for EV in neonates suspected to have sepsis, but with sterile bacterial cultures. Results Cases were identified in each of three sequential years in a NICU with 800 to 900 admissions/year. Two cases were likely acquired perinatally; all were symptomatic with lethargy and poor feeding by age 5 to 10 days. All had signs of sepsis and/or meningitis; one progressed to periventricular leukomalacia and encephalomalacia. Two recovered from myocarditis after treatment that included IVIG 3 to 5 g/kg. Conclusion Neonates who appear septic without bacterial etiology may have EV CNS infections that can be diagnosed rapidly by CSF PCR testing. Cases may be underdiagnosed in the early neonatal period if specific testing is not performed. Neonates with EV infection should be investigated for evidence of periventricular leukomalacia, screened for myocarditis, and considered for IVIG treatment.

Wait-List Outcomes for Adults With Congenital Heart Disease Listed for Heart Transplantation in the U.S.

BACKGROUND: Heart failure represents a common end-stage syndrome for many adults with congenital heart disease (ACHD). These patients, however, have been excluded from most heart transplantation research. It is not known how current criteria, derived from non-ACHD populations, used to determine priority at the time of transplant listing, impact the outcomes for ACHD patients listed for heart transplantation. OBJECTIVES: The goal of this study was to investigate outcomes of ACHD in comparison to non-ACHD patients while listed for heart transplantation. METHODS: We conducted a retrospective study using the Scientific Registry of Transplant Recipients on patients ≥18 years of age listed in the United States between 1999 and 2014. The probability of mortality or delisting due to clinical worsening was estimated using cumulative incidence functions, where transplantation was a competing event. RESULTS: Among 1,290 ACHD and 38,557 non-ACHD patients listed, 237 ACHD and 6,377 non-ACHD patients died or were delisted due to clinical worsening. Death or delisting for clinical worsening was more likely for ACHD patients initially listed as status 1A (24% ACHD vs. 17% non-ACHD after 180 days; p < 0.001). There were no significant differences between ACHD and non-ACHD patients listed as status 1B or 2. In multivariable analysis, factors associated with death or delisting due to clinical worsening within 1 year in ACHD included: estimated glomerular filtration rate <60 ml/min/1.73 m(2) (hazard ratio [HR]: 1.4; 95% confidence interval [CI]: 1.0 to 1.9; p = 0.043); albumin <3.2 g/dl (HR: 2.0; 95% CI: 1.3 to 2.9; p <0.001); and hospitalization at the time of listing, whether in the intensive care unit (HR: 2.3; 95% CI: 1.6 to 3.5; p < 0.001) or not (HR: 1.9; 95% CI: 1.2 to 3.0; p = 0.006) relative to outpatients. CONCLUSIONS: Wait-list mortality or delisting due to worsening clinical status is disproportionately common for ACHD patients listed as status 1A. An allocation system that takes into account the distinctive aspects of ACHD patients may help better care for this growing population.

Aip1p dynamics are altered by the R256H mutation in actin.

Mutations in actin cause a range of human diseases due to specific molecular changes that often alter cytoskeletal function. In this study, imaging of fluorescently tagged proteins using total internal fluorescence (TIRF) microscopy is used to visualize and quantify changes in cytoskeletal dynamics. TIRF microscopy and the use of fluorescent tags also allows for quantification of the changes in cytoskeletal dynamics caused by mutations in actin. Using this technique, quantification of cytoskeletal function in live cells valuably complements in vitro studies of protein function. As an example, missense mutations affecting the actin residue R256 have been identified in three human actin isoforms suggesting this amino acid plays an important role in regulatory interactions. The effects of the actin mutation R256H on cytoskeletal movements were studied using the yeast model. The protein, Aip1, which is known to assist cofilin in actin depolymerization, was tagged with green fluorescent protein (GFP) at the N-terminus and tracked in vivo using TIRF microscopy. The rate of Aip1p movement in both wild type and mutant strains was quantified. In cells expressing R256H mutant actin, Aip1p motion is restricted and the rate of movement is nearly half the speed measured in wild type cells (0.88 ± 0.30 µm/sec in R256H cells compared to 1.60 ± 0.42 µm/sec in wild type cells, p < 0.005).

Thoracic aortic aneurysm (TAAD)-causing mutation in actin affects formin regulation of polymerization.

More than 30 mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause autosomal dominant thoracic aortic aneurysm and dissection. The mutation R256H is of particular interest because it also causes patent ductus arteriosus and moyamoya disease. R256H is one of the more prevalent mutations and, based on its molecular location near the strand-strand interface in the actin filament, may affect F-actin stability. To understand the molecular ramifications of the R256H mutation, we generated Saccharomyces cerevisiae yeast cells expressing only R256H yeast actin as a model system. These cells displayed abnormal cytoskeletal morphology and increased sensitivity to latrunculin A. After cable disassembly induced by transient exposure to latrunculin A, mutant cells were delayed in reestablishing the actin cytoskeleton. In vitro, mutant actin exhibited a higher than normal critical concentration and a delayed nucleation. Consequently, we investigated regulation of mutant actin by formin, a potent facilitator of nucleation and a protein needed for normal vascular smooth muscle cell development. Mutant actin polymerization was inhibited by the FH1-FH2 fragment of the yeast formin, Bni1. This fragment strongly capped the filament rather than facilitating polymerization. Interestingly, phalloidin or the presence of wild type actin reversed the strong capping behavior of Bni1. Together, the data suggest that the R256H actin mutation alters filament conformation resulting in filament instability and misregulation by formin. These biochemical effects may contribute to abnormal histology identified in diseased arterial samples from affected patients.

Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy.

BACKGROUND: The importance of clinical presentation and pretransplantation course on outcome in children with dilated cardiomyopathy listed for heart transplantation is not well defined. METHODS AND RESULTS: The impact of age, duration of illness, sex, race, ventricular geometry, and diagnosis of myocarditis on outcome in 261 children with dilated cardiomyopathy enrolled in the Pediatric Cardiomyopathy Registry and Pediatric Heart Transplant Study was studied. End points included listing as United Network for Organ Sharing status 1, death while waiting, and death after transplantation. The median age at the time of diagnosis was 3.4 years, and the mean time from diagnosis to listing was 0.62±1.3 years. Risk factors associated with death while waiting were ventilator use and older age at listing in patients not mechanically ventilated (P=0.0006 and P=0.03, respectively). Shorter duration of illness (P=0.04) was associated with listing as United Network for Organ Sharing status 1. Death after transplantation was associated with myocarditis at presentation (P=0.009), nonwhite race (P<0.0001), and a lower left ventricular end-diastolic dimension z score at presentation (P=0.04). In the myocarditis group, 17% (4 of 23) died of acute rejection after transplantation. CONCLUSIONS: Mechanical ventilator use and older age at listing predicted death while waiting, whereas nonwhite race, smaller left ventricular dimension, and myocarditis were associated with death after transplantation. Although 97% of children with clinically or biopsy-diagnosed myocarditis at presentation survived to transplantation, they had significantly higher posttransplantation mortality compared with children without myocarditis, raising the possibility that preexisting viral infection or inflammation adversely affects graft survival.