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While de novo donor-specific HLA antibodies (dnDSAs) have a detrimental impact on kidney graft outcome, the clinical significance of de novo non donor-specific antibodies (dnNDSAs) is more controversial. We retrospectively evaluated for Ab development and characteristics of dnNDSAs serially collected post-transplant sera and, when available, graft biopsy eluates, from 144 non-sensitized, primary pediatric kidney recipients, consecutively transplanted at a single center between 2003 and 2017, using HLA class I and class II single-antigen flow-bead assays (SAB). The results were compared with clinical-pathologic data from HLA antibody negative and HLA dnDSA-positive patients. Forty-five out of 144 patients developed dnNDSAs (31%). Among the dnNDSA-positive patients, 86% displayed one or more class I/II antibodies recognizing antigens included in the CREG/shared epitope groups that also comprise the mismatched donor HLA antigens. Despite potential pathogenicity, as suggested by their occasional presence within the graft, dnNDSAs displayed significantly lower MFI, and limited complement binding and graft homing properties, when compared with dnDSAs. In parallel, the graft survival probability was significantly lower in patients with dnDSA than in those with dnNDSA or without HLA antibodies (p < 0.005). Indeed, the dnNDSA-positive patients remaining dnDSA-negative throughout the posttransplant period did not develop clinical antibody mediated rejection and graft loss, and maintained good graft function at a median follow-up of 9 years. The biological characteristics of dnNDSAs may account for the low graft damaging capability when compared to dnDSAs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Takotsubo cardiomyopathy is a reversible cardiomyopathy, which generally developes in menopausal women and is characterized by left ventricle dysfunction with apical ballooning in the absence of coronary artery disease. It is often triggered by a stressful event, and its clinical presentation resembles acute anterior myocardial infarction. This condition is a rare adverse event of cardiac operations, and only a few cases are described in the literature, especially after mitral valve operations. We report the case of a 69-year-old man who underwent aortic valve repair and ascending aorta replacement, followed by pericardial effusion 6 months later, requiring pericardiocentesis resulting in Takotsubo cardiomyopathy., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complement-binding ability of de novo donor-specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement-fixing dnDSAs and their role in antibody-mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q(+) and C3d(+) in 25 and nine patients, respectively. At follow-up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d-fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10-year graft survival probability was lower in patients with C3d-binding dnDSA than in those without dnDSAs or with C1q(+) /C3d(-) or non-complement-binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus-associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV-specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4(+) T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV-specific CD8(+) T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty-nine EVGR epitopes were experimentally confirmed by interferon-γ enzyme-linked immunospot assays in at least 30% of BKPyV IgG-seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer., (© 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

Objectives: This study sought to evaluate the impact of baseline activated clotting time (ACT)-guided heparin administration on major bleeding after transfemoral transcatheter aortic valve implantation (TAVI)., Background: Bleeding after TAVI is frequent and associated with unfavorable prognosis. Proper intraprocedural heparin dose administration may reduce the risk of potential overdosing in this frail study group., Methods: Of the patients who underwent transfemoral TAVI in our center from November 1, 2007 to June 31, 2012, 362 were retrospectively analyzed. Because abnormally high baseline ACT values were noted, heparin was administered at the operator's discretion, according to baseline ACT (ACT-guided, n = 174) or patient's body weight (non-ACT-guided, n = 188). The primary study objective was 30-day major bleeding as defined by the Valve Academic Research Consortium criteria. Secondary objectives were any life-threatening, and minor bleeding, and other Valve Academic Research Consortium outcomes at 30 days., Results: Bleeding occurred in 167 (46.1%) patients; of these, 76 (21.0%) had major bleeding. The ACT-guided group had a significantly lower occurrence of major (7.5% vs. 33.5%, p < 0.001), life-threatening (12.1% vs. 20.2%, p = 0.04), and any bleeding (25.9% vs. 64.9%, p < 0.001). Conversely, no differences were noted in the other study objectives. After adjustment for potential confounders, the protective odds ratio for ACT-guided therapy on major bleeding was 6.4 (95% confidence interval: 2.3 to 17.9; p < 0.001) at 30 days., Conclusions: In our experience, heparin administration according to baseline ACT was correlated with a significantly lower occurrence of major bleeding in transfemoral TAVI. This strategy might be a useful tool in reducing bleeding in this high-risk study group., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: TAVI is the alternative option in pts with AS deemed ineligible for surgery. Although mortality and morbidity are measures to assess the effectiveness of treatments, quality of life (QOL) should be an additional target. We assessed clinical outcome and QOL in octogenarians following TAVI., Design: All octogenarians with a risk profile considered by the Heart Team to be unacceptable for surgery entered in this registry. QOL was assessed by questionnaires concerning physical and psychic performance., Patients: A hundred forty-five octogenarians (age: 84.7 ± 3.4 years; male: 48.3%) underwent TAVI for AS (97.2%) or isolated AR (2.8%). NYHA class: 2.8 ± 0.6; Logistic EuroScore: 26.1 ± 16.7; STS score: 9.2 ± 7.7.Echocardiographic assessments included AVA (0.77 ± 0.21 cm2), mean/peak gradients (54.5 ± 12.2/88 ± 19.5 mm Hg), LVEF (21%=EF ≤ 40%), sPAP (43.1 ± 11.6 mmHg)., Interventions: All pts underwent successful TAVI using Edward-SAPIEN valve (71.2%) or Medtronic CoreValve (28.8%)., Main Outcome Measures: Rates of mortality at 30 days, 6 months and 1 year were 2.8%, 11.2% and 17.5%., Results: At 16-month follow up, 85.5% survived showing improved NYHA class (2.8 ± 0.6 vs 1.5 ± 0.7; p<0.001), decreased sPAP (43.1 ± 11.6 mm Hg vs 37.1 ± 7.7 mm Hg; p<0.001) and increased LVEF in those with EF ≤ 40% (34.9 ± 6% vs 43.5 ± 14.4%; p=0.006). Concerning QOL, 49% walked unassisted, 79% (39.5% among pts ≥ 85 years) reported self-awareness improvement; QOL was reported as "good" in 58% (31.4% among pts ≥ 85 years), "acceptable according to age" in 34% (16% among pts ≥ 85 years) and "bad" in 8%., Conclusion: TAVI procedures improve clinical outcome and subjective health-related QOL in very elderly patients with symptomatic AS., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Transcatheter aortic valve implantation (TAVI) has been proposed as a therapeutic option for high-risk or inoperable patients with severe symptomatic aortic valve stenosis. The aim of this multicenter study was to assess early and medium term outcomes of transapical aortic valve implantation (TA-TAVI)., Methods: From April 2008 through June 2012, a total of 774 patients were enrolled in the Italian Registry of Trans-Apical Aortic Valve Implantation (I-TA). Twenty-one centers were included in the I-TA registry. Outcomes were also analyzed according to the impact of the learning curve (first 50% cases versus second 50% cases of each center) and of the procedural volume (high-volume versus low-volume centers)., Results: Mean age was 81.0±6.7 years, mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I, EuroSCORE II, and The Society of Thoracic Surgeons risk score were 25.6%±16.3%, 9.4%±11.0%, and 10.6%±8.5%, respectively. Median follow-up was 12 months (range, 1 to 44). Thirty-day mortality was 9.9% (77 patients). Overall 1-, 2-, and 3-year survival was 81.7%±1.5%, 76.1%±1.9%, and 67.6%±3.2%, respectively. Thirty-day mortality of the first 50% patients of each center was higher when compared with the second half (p=0.04) but 3-year survival was not different (p=0.64). Conversely, 30-day mortality at low-volume centers versus high-volume centers was similar (p=0.22). At discharge, peak and mean transprosthetic gradients were 21.0±10.3 mm Hg and 10.2±4.1 mm Hg, respectively. These values remained stable 12 and 24 months after surgery., Conclusions: Transapical TAVI provides good results in terms of early and midterm clinical and hemodynamic outcomes. Thus it appears to be a safe and effective alternative treatment for patients who are inoperable or have high surgical risk., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: The aim of this study was to explore the incidence, causes, and outcomes of cardiac tamponade in patients undergoing transcatheter aortic valve implantation (TAVI)., Background: Use of TAVI is increasing, but the procedure is vulnerable to complications, given the cohort of patients. Cardiac tamponade is a possible complication, and there is a scarcity of data on the incidence and outcomes of cardiac tamponade during TAVI., Methods: All patients who sustained cardiac tamponade during or post-TAVI between 2007 and 2012 were included in the study., Results: Of 389 patients who underwent TAVI, 17 (4.3%) had cardiac tamponade. The mean age was 82.3 ± 3.7 years, and most were women (n = 12, 70.6%). Causes of cardiac tamponade were right ventricular perforation by temporary pacemaker (9 patients, 52.9%), annular rupture or aortic dissection (4 patients, 23.5%), and tear in the left ventricular free wall caused by Amplatz stiff wire or catheters (4 patients, 23.5%). Mortality occurred in 4 patients (23.5%), and all had tamponade caused by injury to the high-pressured left-sided circulation (left ventricle and aorta). Most patients (n = 14, 82.4%) sustained cardiac tamponade during the procedure-2 patients (11.7%) within 24 h, and 1 patient after 24 h., Conclusions: Cardiac tamponade during TAVI is not frequent but is associated with high mortality rates especially when left-sided structures are involved. Meticulous handling of the equipment and improvements in the safety of currently used devices could further reduce the occurrence of this complication., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to analyze the short-term outcomes after transcatheter aortic valve implantation with the Edwards Sapien THV (ESV), compared with the Sapien XT THV (SXT) (Edwards Lifesciences, Irvine, California)., Background: The SXT has been recently commercialized in Europe, but there are no studies analyzing the efficacy and safety of SXT, compared with ESV., Methods: All consecutive patients (n = 120) who underwent transcatheter aortic valve implantation in our center via the transfemoral approach with either ESV (n = 66) or SXT (n = 54). Valve Academic Research Consortium endpoints were used., Results: Mean age was 80 ± 8 years, and mean Logistic-European System for Cardiac Operative Risk Evaluation was 24.9 ± 17.0. The ilio-femoral artery minimal lumen diameter was smaller in patients treated with the SXT (7.27 ± 1.09 mm vs. 7.94 ± 1.08 mm, p = 0.002). Device success was high in both groups (96.3% vs. 92.4%, p = 0.45). Major vascular events were 3-fold lower in the SXT group (11.1% vs. 33.3%, relative risk: 0.40, 95% confidence interval: 0.28 to 0.57; p = 0.004). Life-threatening and major bleeding events were not significantly different between groups (18.5% vs. 27.3% and 35.2% vs. 40.9%, respectively). The SXT group had a lower 30-day Valve Academic Research Consortium combined safety endpoint (20.4% vs. 45.5%; relative risk: 0.44, 95% confidence interval: 0.24 to 0.80; p = 0.004). The 30-day mortality was 1.7% (n = 2). At 30 days, mean transaortic gradient was approximately 10 mm Hg in both groups and the aortic regurgitation was mild-to-moderate in 70.2% of SXT and 76.3% of ESV., Conclusions: The new SXT valve has the same short-term performance as the ESV but seems to be associated with a lower risk of major vascular complications and thus has a broader clinical application., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Our aim was to assess clinical outcome after transcatheter aortic valve implantation (TAVI) performed with the 2 commercially available valves with 3 delivery approaches selected in a stepwise fashion., Background: Limited data exist on the results of a comprehensive TAVI program using different valves with transfemoral, transapical, and transaxillary approaches for treatment of severe aortic stenosis., Methods: We report 30-day and 6-month outcomes of high-risk patients consecutively treated in a single center with either the Medtronic-CoreValve (MCV) (Medtronic, Minneapolis, Minnesota) or Edwards-SAPIEN valve (ESV) (Edwards Lifesciences, Irvine, California) delivered via the transfemoral or transaxillary approaches and ESV via the transapical approach., Results: A total of 137 patients underwent TAVI: 107 via transfemoral (46 MCV and 61 ESV), 15 via transaxillary (12 MCV and 3 ESV), and 15 via transapical approach. After the transfemoral approach, the procedural success rate was 93.5%, and major vascular complication rate was 20.6%. No intra-procedural deaths occurred. The procedural success rates of transapical and transaxillary approaches were 86.6% and 93.3%, respectively. The 30-day mortality rate was 0.9% in transfemoral group and 13.3% in transapical, and no deaths occurred after transaxillary access. Cumulative death rate at 6 months was 12.2% in transfemoral, 26.6% in transapical, and 18.2% in transaxillary groups. At multivariable analysis, logistic European System for Cardiac Operative Risk Evaluation, body surface area, and history of cerebrovascular disease were significantly associated with an increased risk of major adverse cardiac and cerebrovascular events., Conclusions: Routine TAVI using both MCV and ESV with a selection of approaches is feasible and allows treatment of a wide range of patients with good overall procedural success rates and 30-day and 6-month outcomes., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We report a patient with mental retardation, epilepsy, overgrowth, delayed bone age, peculiar facial features, corpus callosum hypoplasia, enlarged cisterna magna and right cerebellar hypoplasia. Array-CGH analysis revealed the presence of a de novo 3.2 Mb interstitial deletion of the long arm of chromosome 7 involving bands q22.2-q22.3. The rearrangement includes 15 genes and encompasses a genomic region that represents a site of frequent loss of heterozygosity in myeloid malignancies. Four genes are implicated in the control of cell cycle: SRPK2, MLL5, RINT1 and LHFPL3. Haploinsufficiency of these genes might therefore be associated with overgrowth and could confer susceptibility to cancers or other tumours, so that attention to this possibility would be appropriate during regular medical review. In conclusion, array-CGH analysis should be performed in patients with overgrowth where the known causes have already been excluded, because some still unclassified overgrowth syndromes may be caused by subtle genomic imbalances., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Unlabelled: AIMS AND STUDY DESIGN: The Hammersmith Infant Neurological Examination proved effective in predicting locomotor function in very preterm infants after 9 months of age. We performed the examination in a cohort of 103 very preterm infants (gestational age below 32 weeks) as early as 3 months' post-term age, and longitudinally at 6, 9 and 12 months. Our aim was to establish the frequency distribution of the optimality scores at each age period, to explore the predictive value of the examination from 3 months onwards as to developmental outcome and locomotor function at 2 years, and to explore its longitudinal consistency., Results: The results showed that this standardized neurological examination can be performed in preterm infants as early as 3 months' post-term age to predict motor outcome at 2 years, and that its high predictive value is consistent across the first year of life due to an effective combination of different items for each age period., Conclusions: We confirm the high predictive value of this neurological examination in very preterm infants after 9 months and extend it to the assessments performed as early as 3 months post-term. This is of great relevance as in very preterm infants early prediction of motor function is essential for a prompt planning of therapeutic interventions.

Polyoma BK virus (BKV)-associated nephropathy (PVAN) is a relevant cause of poor renal allograft survival. In a prospective analysis, we monitored BKV DNA in blood and urine samples from 62 consecutive pediatric kidney recipients. In patients with BKV replication, we analyzed the impact of reduction of maintenance immunosuppression on viral load kinetics and PVAN in patients with BKV replication. BKV-specific immunity was concomitantly evaluated on blood samples of viremic patients, by measuring the frequency of BKV-specific interferon-gamma-producing and cytotoxic T cells, and BKV IgG antibody levels. At a median follow-up of 24 months, BK viruria was observed in 39 of 62 patients, while BK viremia developed in 13 patients (21%). In all viremic patients, immunosuppression reduction resulted in the clearance of viremia, and prevented development of PVAN, without increasing the rate of acute rejection or causing graft dysfunction. As a consequence of immunosuppression adjustment, an expansion of BKV-specific cellular immunity was observed that coincided with viral clearance. We conclude that treating pediatric kidney transplant patients pre-emptively with immunosuppression reduction guided by BKV DNA in blood is safe and effective to prevent onset of PVAN. BKV-specific cellular immunity may be useful to guide this intervention.

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Schinzel-Giedion syndrome (SGS) is a rare disorder with a likely autosomal recessive pattern of inheritance which is characterized by several facial dysmorphisms, midface hypoplasia, multiple skeletal anomalies including short and sclerotic skull base, short neck, and post-axial polydactyly. Cardiac and urogenital malformations are also present. Thirty-three cases have been described so far. We report on a boy affected by SGS in whom a long-term EEG follow-up showed a progressive deterioration of the background bioelectric activity ending, at the age of 19 months, with a hypsarrhythmic pattern clinically correlated with severe and refractory infantile spasms. EEG deterioration and neuroradiological findings, which showed progressive brain atrophy, confirm the neurodegenerative nature of SGS. We also re-evaluated all the published cases and found that 33% of patients with SGS experienced neonatal seizures and another 25% developed West syndrome in the following months. The seizures appeared extremely refractory to several anticonvulsive treatments. In conclusion, we believe that SGS should be included among the causes of secondary West syndrome.

Intracranial calcification and microcephaly, which represent the main clinical features of the TORCH-syndrome, can also be determined by a rare autosomal recessive infection-like condition named pseudo-TORCH syndrome. This emerging entity has been registered in eight families so far. We report on five patients from three unrelated Italian families affected by pseudo-TORCH syndrome. Reevaluation of literature allowed us to draw a specific clinical profile of the syndrome. Indeed, congenital microcephaly, congenital cerebral calcification, spasticity and seizures are the main clinical features, and have been present in almost all patients reported so far. On the contrary, findings resembling congenital infectious diseases including neonatal icterus, hyperbilirubinemia, thrombocytopenia, and hepatomegaly, affect less than half of the patients. Considering the diagnosis of pseudo-TORCH syndrome in patients with neonatal microcephaly and cerebral calcification is necessary since an early diagnosis may allow adequate genetic counseling to the families.