A machine-learning method isolating changes in wrist kinematics that identify age-related changes in arm movement.

Normal aging often results in an increase in physiological tremors and slowing of the movement of the hands, which can impair daily activities and quality of life. This study, using lightweight wearable non-invasive sensors, aimed to detect and identify age-related changes in wrist kinematics and response latency. Eighteen young (ages 18-20) and nine older (ages 49-57) adults performed two standard tasks with wearable inertial measurement units on their wrists. Frequency analysis revealed 5 kinematic variables distinguishing older from younger adults in a postural task, with best discrimination occurring in the 9-13 Hz range, agreeing with previously identified frequency range of age-related tremors, and achieving excellent classifier performance (0.86 AUROC score and 89% accuracy). In a second pronation-supination task, analysis of angular velocity in the roll axis identified a 71 ms delay in initiating arm movement in the older adults. This study demonstrates that an analysis of simple kinematic variables sampled at 100 Hz frequency with commercially available sensors is reliable, sensitive, and accurate at detecting age-related increases in physiological tremor and motor slowing. It remains to be seen if such sensitive methods may be accurate in distinguishing physiological tremors from tremors that occur in neurological diseases, such as Parkinson's Disease.

Anaerobic Fungal Mevalonate Pathway Genomic Biases Lead to Heterologous Toxicity Underpredicted by Codon Adaptation Indices.

Anaerobic fungi are emerging biotechnology platforms with genomes rich in biosynthetic potential. Yet, the heterologous expression of their biosynthetic pathways has had limited success in model hosts like E. coli. We find one reason for this is that the genome composition of anaerobic fungi like P. indianae are extremely AT-biased with a particular preference for rare and semi-rare AT-rich tRNAs in E coli, which are not explicitly predicted by standard codon adaptation indices (CAI). Native P. indianae genes with these extreme biases create drastic growth defects in E. coli (up to 69% reduction in growth), which is not seen in genes from other organisms with similar CAIs. However, codon optimization rescues growth, allowing for gene evaluation. In this manner, we demonstrate that anaerobic fungal homologs such as PI.atoB are more active than S. cerevisiae homologs in a hybrid pathway, increasing the production of mevalonate up to 2.5 g/L (more than two-fold) and reducing waste carbon to acetate by ~90% under the conditions tested. This work demonstrates the bioproduction potential of anaerobic fungal enzyme homologs and how the analysis of codon utilization enables the study of otherwise difficult to express genes that have applications in biocatalysis and natural product discovery.

Pediatric Cardiac Critical Care Transport and Palliative Care: A Case Series.

OBJECTIVE: To present our center's experience with terminal extubation in 3 palliative critical care home transports from the Pediatric Cardiac Intensive Unit. DESIGN: All cases were identified from our Cardiovascular intensive care unit ( CVICU). Patients were terminally ill children with no other surgical or medical option who were transported home between 2014 and 2018, for terminal extubation and end-of-life care according to their families' wishes. INTERVENTIONS: The patients were 7, 9 months, and 19 years; and they had very complex and chronic conditions. The families were approached by the CVICU staff during multidisciplinary meetings, where goals of care were established. Parental expectations were clarified, and palliative care team was involved, as well as home hospice was arranged pre transfer. The transfer process was discussed and all the needs were established. All patients had unstable medical conditions, with needs for transport for withdrawal of life support and death at home. Each case needed a highly trained team to support life while in transport. The need of these patients required coordination with home palliative care services, as well as community resources due to difficulty to get in their homes. CONCLUSIONS: Transportation of pediatric cardiac critical care patients for terminal extubation at home is a relatively infrequent practice. It is a feasible alternative for families seeking out of the hospital end-of-life care for their critically ill and technology dependent children. Our single-center experience supports the need for development of formal programs for end-of-life critical care transports.

Alkaline Phosphatase: A Biomarker of Cardiac Function in Pediatric Patients.

Myocardial dysfunction and heart failure are common in pediatric patients with congenital and acquired heart disease. Alkaline phosphatase (AP) has been suggested as a biomarker for myocardial dysfunction after Fontan operation. We hypothesized that pediatric patients with myocardial dysfunction requiring orthotopic heart transplant (OHT) have diminished AP compared to normal. A retrospective review was performed in all patients who underwent OHT at Arkansas Children's Hospital between January 2007 and October 2012. Anatomic diagnoses, therapeutic interventions, and ventricular ejection fraction (EF) were recorded. Z scores for AP levels in the study group were determined by comparing the observed AP levels to age- and gender-matched normative values. T tests were performed to compare the mean AP Z score prior to and after OHT. p values <0.05 were considered statistically significant. During the study period, 124 OHTs were performed. Complete study data were available and analyzed from 71/124 patients (mean age at OHT 3.9 years; 51% female). The mean AP Z score was significantly lower in the study group prior to OHT compared to normal (p < 0.0001). The initiation of ACE inhibitor therapy prior to OHT was associated with a significant increase in AP and the ventricular EF (p < 0.001 for both). Treatment with milrinone was associated with an increase in EF. AP is significantly lower in pediatric patients with myocardial dysfunction prior to OHT compared to normal. AP increases significantly after the initiation of therapies to improve myocardial function. Diminished AP is an indicator of myocardial dysfunction in pediatric patients.

Improved Survival While Waiting and Risk Factors for Death in Pediatric Patients Listed for Cardiac Transplantation.

Our aim is to determine (a) the effect of changes in pre-transplant management and era of listing on survival of children listed for HTx and (b) risk factors for death while waiting. This retrospective study included all children listed between 1/1993 and 12/2009 at our center. Survival was determined using survival analysis and competing outcomes modeling. There were 254 listed patients of whom 144 (57%) had congenital heart disease, 208 (82%) were status 1, 52 used ECMO (20%), and 28 used ventricular assist device support (VAD) (11%) beginning in 2005. Overall mortality while waiting was 17% at 6 months, and 69% underwent transplant. Seven of 95 patients (7%) died waiting after 2004 compared to 36 of 159 (23%) before. ECMO and earlier year of listing were significant risk factors (p < 0.001) for wait-list mortality, whereas mortality was significantly lower (p = 0.002) after availability of VADs. Race, gender, blood type, and congenital diagnosis were not significant risk factors for death. Survival in pediatric patients listed for HTx has improved significantly in the current era at our institution. The availability of pediatric VADs has had a significant impact on survival while waiting in children listed for transplantation.

Aortic complications following pediatric heart transplantation: A case series and review.

Aortic complications occur rarely after pediatric orthotopic heart transplantation, but are typically accompanied by catastrophic events. We describe the three cases of major aortic complications in our experience of 329 pediatric heart transplants. This case series and review highlight the important risk factors for aortic complications after heart transplantation.

Risk factors for prolonged mechanical ventilation for children on ventricular assist device support.

BACKGROUND: Patients with end-stage heart failure possess many attributes that place them at risk for prolonged mechanical ventilation (MV). However, there are only limited data on MV support among children after ventricular assist device (VAD) implantation. We report the duration of MV after VAD placement, indications for respiratory support in the postimplantation period, and associated patient factors. METHODS: This single-center retrospective study included 43 consecutive children (aged <18 years) with end-stage heart failure who were supported with a VAD as a bridge to transplantation from January 2005 to December 2011. Multivariable analysis was performed using the multiple Poisson regression model for the duration of MV. RESULTS: Overall, 33% (n = 14) remained on MV until heart transplant or death. Of those requiring pre-VAD extracorporeal membrane oxygenation (ECMO) support, 63% (n = 12 of 19) remained on MV until heart transplant or death compared with 8% (n = 2 of 24) among those not on ECMO before VAD (p < 0.001). Patients with moderate or severe mitral regurgitation while on VAD support had 1.7-times more MV days compared with those with none or trivial on-VAD mitral regurgitation. In addition, previous support on ECMO, those with moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. CONCLUSIONS: Our results suggest that VAD recipients previously supported on ECMO, those with moderate or severe mitral regurgitation, moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. Future studies in larger cohorts are necessary to confirm the findings from this single-institutional experience.

Heart Transplantation in the Short Term After Chemotherapy.

Anthracycline antibiotics are an effective therapy for a variety of neoplastic diseases. Dilated cardiomyopathy is a known risk of their use. Because of the risk of new or recurrent neoplasm with immunosuppression transplantation is often delayed. Our patient developed early cardiomyopathy with congestive heart failure 3 months after completion of chemotherapy. Given the severity of her cardiac symptoms the decision was made to proceed with heart transplantation in the short term after completion of her chemotherapy. We report the success to 1 year of this decision and discuss the implications of her genetic and oncologic diagnoses in this clinical scenario.

Hemorrhage requiring surgical intervention among children on pulsatile ventricular assist device support.

Bleeding complications are a source of morbidity after Berlin EXCOR VAD implantation yet remain poorly characterized. We evaluated our experience to describe the bleeding complications among pediatric VAD recipients. We hypothesized that those with bleeding requiring exploration had abnormal coagulation profile compared with those without bleeding. The retrospective study included 43 consecutive patients with end-stage heart failure supported on pediatric mechanical cardiac support as a bridge to transplantation. Day-/event-based analysis on factors below associated with (i) bleeding and (ii) bleeding in next 48 h. Cases with bleeding were compared with day-matched patients without bleeding complications. Among 43 subjects bleeding occurred in 47% of cases, which necessitated exploration or chest tube placement. Twenty of 34 interventions for bleeding occurred in the first seven post-operative days. No differences in coagulation parameters or use of antiplatelet agents were noted among those who had bleeding vs. those who did not. Our results indicate that (i) re-bleeding requiring re-exploration was common, (ii) most of the bleeding occurred early post-implantation, (iii) there were no differences in coagulation parameters or the use of antiplatelet agents within 48 h of bleeding compared with those who did not bleed on each successive post-operative day.

New transplant technique with hemiazygos continuation and interrupted inferior vena cava.

In the presence of left superior vena cava, cardiac transplantation is performed at the risk of left superior vena cava flow obstruction. In patients with hemiazygos continuation with interrupted inferior vena cava, the patency of left superior vena cava is vital. We introduced a new surgical technique to use a Fontan connection including the native central pulmonary artery as the systemic venous return. The pulmonary artery anastomosis was performed distal to the superior vena cava anastomosis sites. We used this treatment approach successfully to perform cardiac transplantation in two patients who developed severe heart failure after Fontan completion.

Quantification, identification, and relevance of anti-human leukocyte antigen antibodies formed in association with the berlin heart ventricular assist device in children.

BACKGROUND: Ventricular assist devices (VADs) are increasingly being used in pediatric patients to provide long-term cardiac support. One potential complication of VAD therapy is the development of antibodies directed against human leukocyte antigens (HLA). This phenomenon has not been well described with the Berlin Heart EXCOR VAD, the most commonly used VAD in pediatric patients. METHODS: The records of all pediatric patients undergoing VAD support using the Berlin Heart device at our institution between April 2005 and August 2011 were reviewed retrospectively. Demographic and clinical data regarding the VAD course were collected. Assessment of anti-HLA antibodies was performed using Luminex, and antibodies were quantified using mean fluorescence intensity (MFI). Assessment for anti-HLA antibodies was performed before VAD implantation and in serial fashion after VAD implantation. Clinically significant anti-HLA antibodies (sensitization) were defined by an MFI of more than 1000. RESULTS: Thirty-six patients were supported with the Berlin Heart VAD; 13 met inclusion criteria. The majority (85%) carried the diagnosis of dilated cardiomyopathy. Evidence of sensitization pre-VAD was found in 69%; new-onset sensitization (the development of new antibodies on VAD) occurred in 69%. All patients survived to transplantation. In two patients, the retrospective crossmatch was positive, but only in one patient was the crossmatch positive for antibodies formed while on VAD. CONCLUSIONS: Using Luminex and MFI quantification, anti-HLA antibodies are common before VAD implantation in pediatric patients. While on VAD support, new anti-HLA antibodies formed in a majority, but the immediate impact of these antibodies appears to be limited.

Echocardiographic evaluation of ventricular assist devices in pediatric patients.

BACKGROUND: The use of ventricular assist devices (VADs) in children is challenging because of small patient size, frequent structural heart disease, and the need for biventricular assist devices. This report describes the role of echocardiography in the management of children supported by VADs. METHODS: A retrospective review of the records of all pediatric patients who underwent VAD placement between May 2005 and May 2011 was performed to collect demographics, cardiac diagnoses, details of VADs, and transthoracic and transesophageal echocardiographic findings from the time of initial diagnosis until VAD explantation. RESULTS: The study included 32 patients (median age, 3 years; age range, 20 days to 16 years; median weight, 12.3 kg; weight range, 3.5-60 kg), 20 with left ventricular assist devices and 12 with biventricular assist devices. Diagnoses included dilated cardiomyopathy or myocarditis (n = 27) and congenital heart disease (n = 5). The median duration of support was 12 days (range, 1-141 days). Patients with decreased right ventricular function were 8 times more likely to undergo biventricular assist device placement compared with those with normal right ventricular function (P = .026). Pre-VAD intracardiac shunts were identified in 11 patients and intracardiac thrombus in one patient. Cardiac chamber dimensions and mitral insufficiency were significantly reduced after VAD implantation. Postimplantation pericardial effusions were recognized in 16 patients and pericardial hematomas in 12 patients. CONCLUSIONS: Echocardiography is invaluable in the management of pediatric patients receiving VADs. It is helpful in pre-VAD assessment, guiding intraoperative device placement, recognizing VAD dysfunction, and identifying postimplantation complications.

Parvovirus B19 myocarditis causes significant morbidity and mortality in children.

Although parvovirus B19 (PVB19) currently is the most common cause of viral myocarditis, limited pediatric data exist. Whereas other viruses infect cardiomyocytes, PVB19 targets coronary endothelium, leading to myocardial ischemia and dysfunction. A retrospective review investigated patients with polymerase chain reaction (PCR)-verified PVB19 myocarditis at Texas Children's Hospital and Arkansas Children's Hospital (January 2005 to August 2008). The primary end points of the study were transplant-free survival and circulatory collapse (death, mechanical support, or transplantation). For the 19 patients identified (age, 6 months to 15 years), the most common presenting symptoms were respiratory and gastrointestinal. At admission, all the patients demonstrated ventricular dysfunction requiring inotropic support (median ejection fraction, 24 %; median left ventricle end-diastolic diameter [LVEDD] z-score, 4.6). Whereas T-wave abnormalities were common, ST elevation was evident in five patients (two died and three required transplantation). Serum B-type natrietic peptide was elevated in all 12 patients tested (range, 348-8,058 pg/ml), and troponin I was high in 7 of 9 patients (range, 0.04-14.5 ng/ml). Of the 15 patients with circulatory collapse, nine received mechanical support, eight underwent successful transplantation, and five died. Only six patients (32 %) experienced transplant-free survival, and five patients had full recovery of function at discharge. In the transplant-free survival group, ST changes on presenting electrocardiography were less likely (p = 0.03), and the admission LVEDD z-score tended to be lower (3.3 vs 5.6; p = 0.08). In children, PVB19 myocarditis causes significant mortality and morbidity. Although mechanical intervention can support patients in the initial stage of decompensated heart failure, patients with PVB19 myocarditis often demonstrate persistent dysfunction requiring medical therapy and transplantation.

The pseudophosphatase MK-STYX inhibits stress granule assembly independently of Ser149 phosphorylation of G3BP-1.

The pseudophosphatase MK-STYX (mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding protein) has been implicated in the stress response pathway. The expression of MK-STYX inhibits the assembly of stress granules, which are cytoplasmic storage sites for mRNA that form as a protective mechanism against stressors such as heat shock, UV irradiation and hypoxia. Furthermore, MK-STYX interacts with a key component of stress granules: G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1). Because G3BP-1 dephosphorylation at Ser149 induces stress granule assembly, we initially hypothesized that the inhibition of stress granules by MK-STYX was G3BP-1 phosphorylation-dependent. However, in the present study, using MK-STYX constructs and G3BP-1 phosphomimetic or nonphosphorylatable mutants, we show that MK-STYX inhibits stress granule formation independently of G3BP-1 phosphorylation at Ser149. The introduction of point mutations at the 'active site' of MK-STYX that convert serine and phenylalanine to histidine and cysteine, respectively, is sufficient to generate an active enzyme. In separate experiments, we show that this active mutant, MK-STYX(active), has opposite effects to wild-type MK-STYK. Not only does MK-STYX(active) induce stress granules, but also it has the capacity to dephosphorylate G3BP-1. Taken together, these results provide evidence that the pseudophosphatase MK-STYX plays a key role in the cellular response to stress.

Safety and efficacy of dexmedetomidine in children with heart failure.

This retrospective observational study aimed to evaluate the safety and efficacy of dexmedetomidine (DEX) for children with heart failure. The study was conducted in the cardiovascular intensive care unit (CVICU) of a single, tertiary care, academic children's hospital. A retrospective review of the charts for all children (up to 18 years of age) with signs and symptoms consistent with congestive heart failure who received DEX in our CVICU between April 2006 and April 2011 was performed. The patients were divided into two groups for study purposes: the DEX group of 21 patients, who received a DEX infusion together with other conventional sedation agents, and the control group of 23 patients, who received conventional sedation agents without the use of DEX. To evaluate the safety of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), and inotrope score. To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions in both the DEX and control groups were examined. The numbers of rescue boluses for each category before the initiation of sedative infusion and during the sedative infusion also were examined. The baseline characteristics of the patients in the two groups were similar. There was no effect of DEX infusion on heart rate, MAP, or inotrope score at the termination of infusion. The daily amount of midazolam administered was significantly less during the last 24 h of DEX infusion in the DEX group than in the control group (p = 0.04). The daily amount of morphine infusion did not differ between the DEX and control groups during any period. The numbers of sedation and analgesic rescue boluses were lower in DEX group throughout the infusion. No other significant side effects were noted. Two patients in the DEX group had a 50 % or greater drop in MAP compared with baseline in the first 3 h after initiation of DEX infusion, whereas one patient had a 50 % or greater drop in heart rate compared with baseline in the first 3 h after initiation of DEX infusion. Administration of DEX for children with heart failure appears to be safe but should be used cautiously. Furthermore, DEX use is associated with a decreased opiate and benzodiazepine requirement for children with heart failure.

Solid organ donation in a child after extracorporeal membrane oxygenation, orthotopic heart transplantation, and ventricular assist device support.

Use of high-risk or marginal donors is the most viable short-term means to boost the organ supply and bridge the widening gap between the number of patients on the waiting list for organ transplantation and the insufficient numbers of organ donors. Expansion of the donor pool requires an understanding of the impact on survival likely to result from extending one or more high risk factors. Use of extended donor pool results in shorter waiting list times and limits the morbidity and mortality associated with long-term mechanical support needed to support diseased organs. In this report, we present one such example of expanding donor pool in which a pediatric patient donated a solid organ after two heart transplants and successful use of ECMO and VAD.

NTproBNP as a marker of rejection in pediatric heart transplant recipients.

Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value.

Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients.

BACKGROUND: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS: Patients received four intravenous dose of bortezomib (1.3 mg/m(2)) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

Accidental azygos vein extracorporeal membrane oxygenation cannulation in a neonate with premature closure of the ductus arteriosus.

Our group describes a rare complication of inadvertent azygos vein cannulation during initiation of extracorporeal membrane oxygenation (ECMO) in a neonate with prenatal closure of the ductus arteriosus in a neonate born at an outlying facility and referred for possible congenital heart disease. Upon initial echocardiogram, no flow in the ductus arteriosus was present despite being maintained on prostaglandins. He necessitated ECMO support and the azygos vein was inadvertently cannulated. Lateral chest radiograph suggested placement of cannula in the azygos vein, and this was confirmed by echocardiography. Replacement of venous ECMO cannula with echocardiographic visualization of guide wire position restored ECMO flow. This report emphasizes the importance of lateral chest radiograph and prompt echocardiographic guidance at the time of ECMO cannulation particularly in clinical scenarios associated with azygos vein dilatation or elevated pressures in the right atrium or superior vena cava.