Multivariate phenotype analysis enables genome-wide inference of mammalian gene function.

The function of the majority of genes in the human and mouse genomes is unknown. Investigating and illuminating this dark genome is a major challenge for the biomedical sciences. The International Mouse Phenotyping Consortium (IMPC) is addressing this through the generation and broad-based phenotyping of a knockout (KO) mouse line for every protein-coding gene, producing a multidimensional data set that underlies a genome-wide annotation map from genes to phenotypes. Here, we develop a multivariate (MV) statistical approach and apply it to IMPC data comprising 148 phenotypes measured across 4,548 KO lines. There are 4,256 (1.4% of 302,997 observed data measurements) hits called by the univariate (UV) model analysing each phenotype separately, compared to 31,843 (10.5%) hits in the observed data results of the MV model, corresponding to an estimated 7.5-fold increase in power of the MV model relative to the UV model. One key property of the data set is its 55.0% rate of missingness, resulting from quality control filters and incomplete measurement of some KO lines. This raises the question of whether it is possible to infer perturbations at phenotype-gene pairs at which data are not available, i.e., to infer some in vivo effects using statistical analysis rather than experimentation. We demonstrate that, even at missing phenotypes, the MV model can detect perturbations with power comparable to the single-phenotype analysis, thereby filling in the complete gene-phenotype map with good sensitivity. A factor analysis of the MV model's fitted covariance structure identifies 20 clusters of phenotypes, with each cluster tending to be perturbed collectively. These factors cumulatively explain 75% of the KO-induced variation in the data and facilitate biological interpretation of perturbations. We also demonstrate that the MV approach strengthens the correspondence between IMPC phenotypes and existing gene annotation databases. Analysis of a subset of KO lines measured in replicate across multiple laboratories confirms that the MV model increases power with high replicability.

Outcomes of Neonates Born with Symptomatic Tetralogy of Fallot and Absent Ductus Arteriosus.

OBJECTIVE: To test the hypothesis that neonates with symptomatic tetralogy of Fallot (TOF) and absent ductus arteriosus (ADA) have worse clinical outcomes compared with those with a ductus arteriosus (DA), and that this difference is driven by those born with ADA and with critically deficient pulmonary blood flow (CDPBF). STUDY DESIGN: We performed a retrospective, multicenter cohort study of neonates who underwent intervention for symptomatic TOF comparing death and reintervention between subjects with and without a DA identified on fetal echocardiogram or on echocardiogram performed in the first postnatal day. Exclusion criteria were as follows: inability to define DA status, collaterals supplying pulmonary blood flow, atrioventricular septal defect, and absent pulmonary valve. We defined CDPBF as undergoing a procedure to augment pulmonary blood flow on the date of birth or extracorporeal membrane oxygenation prior to such a procedure. RESULTS: The study cohort included 519 patients, among whom 11% had ADA. Patients with ADA were more likely to have a genetic syndrome and had smaller branch pulmonary artery size. In analyses adjusting for center, interventional treatment strategy, genetic syndrome, and minimum branch pulmonary artery size, ADA was associated with higher mortality risk (adjusted hazard ratio of 2.37 (95% CI: 1.07,5.27; P = .034). Seven patients had CDPBF (1.3% of the entire cohort and 12% of patients with ADA). CONCLUSIONS: A minority of symptomatic TOF neonates have ADA, which is associated with higher adjusted mortality risk compared with those with a DA. CDPBF appears to be a rare but important entity in this population.

A framework for longitudinal latent factor modelling of treatment response in clinical trials with applications to Psoriatic Arthritis and Rheumatoid Arthritis.

OBJECTIVE: Clinical trials involve the collection of a wealth of data, comprising multiple diverse measurements performed at baseline and follow-up visits over the course of a trial. The most common primary analysis is restricted to a single, potentially composite endpoint at one time point. While such an analytical focus promotes simple and replicable conclusions, it does not necessarily fully capture the multi-faceted effects of a drug in a complex disease setting. Therefore, to complement existing approaches, we set out here to design a longitudinal multivariate analytical framework that accepts as input an entire clinical trial database, comprising all measurements, patients, and time points across multiple trials. METHODS: Our framework composes probabilistic principal component analysis with a longitudinal linear mixed effects model, thereby enabling clinical interpretation of multivariate results, while handling data missing at random, and incorporating covariates and covariance structure in a computationally efficient and principled way. RESULTS: We illustrate our approach by applying it to four phase III clinical trials of secukinumab in Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA). We identify three clinically plausible latent factors that collectively explain 74.5% of empirical variation in the longitudinal patient database. We estimate longitudinal trajectories of these factors, thereby enabling joint characterisation of disease progression and drug effect. We perform benchmarking experiments demonstrating our method's competitive performance at estimating average treatment effects compared to existing statistical and machine learning methods, and showing that our modular approach leads to relatively computationally efficient model fitting. CONCLUSION: Our multivariate longitudinal framework has the potential to illuminate the properties of existing composite endpoint methods, and to enable the development of novel clinical endpoints that provide enhanced and complementary perspectives on treatment response.

Impact of Management Strategy on Feeding and Somatic Growth in Neonates with Symptomatic Tetralogy of Fallot: Results from the Congenital Cardiac Research Collaborative.

OBJECTIVE: To evaluate early growth following primary or staged repair of neonatal symptomatic tetralogy of Fallot (sTOF). STUDY DESIGN: We performed a retrospective, multicenter cohort study of consecutive infants with sTOF who underwent initial intervention at age ≤30 days, from 2005 to 2017. Management strategies were either primary repair or staged repair (ie, initial palliation followed by complete repair). The primary outcome was change in weight-for-age z-score (ΔWAZ) from the initial intervention to age 6 ± 2 months. Secondary outcomes included method and mode of feeding, feeding-related medications, and feeding-related readmissions. Propensity score adjustment was used to account for baseline differences between groups. A secondary analysis was performed comparing patients stratified by the presence of adequate growth (6-month ΔWAZ > -0.5) or inadequate growth (6-month ΔWAZ ≤ -0.5), independent of treatment strategy. RESULTS: The study cohort included 143 primary repair subjects and 240 staged repair subjects. Prematurity was more common in the staged repair group. After adjustment, median ΔWAZ did not differ between treatment groups over the first 6 months of life (primary: -0.43 [IQR, -1.17 to 0.50]; staged: -0.31 [IQR, -1.31 to 0.71]; P = .55). For the entire cohort, ΔWAZ was negative (-0.36; IQR, -1.21 to 0.63). There were no between-group differences in the secondary outcomes. Secondary analysis revealed that the subjects with adequate growth were more likely to be orally fed at initial hospital discharge (P = .04). CONCLUSIONS: In neonates with sTOF, growth trajectory over the first 6 months of life was substandard, irrespective of treatment strategy. Those patients with adequate growth were more likely to be discharged from the index procedure on oral feeds.

Interoperability of statistical models in pandemic preparedness: principles and reality.

We present interoperability as a guiding framework for statistical modelling to assist policy makers asking multiple questions using diverse datasets in the face of an evolving pandemic response. Interoperability provides an important set of principles for future pandemic preparedness, through the joint design and deployment of adaptable systems of statistical models for disease surveillance using probabilistic reasoning. We illustrate this through case studies for inferring and characterising spatial-temporal prevalence and reproduction numbers of SARS-CoV-2 infections in England.

Palliation Strategy to Achieve Complete Repair in Symptomatic Neonates with Tetralogy of Fallot.

Neonates with symptomatic tetralogy of Fallot (sTOF) may undergo palliations with varying physiology, namely systemic to pulmonary artery connections (SPC) or right ventricular outflow tract interventions (RVOTI). A comparison of palliative strategies based on the physiology created is lacking. Consecutive sTOF neonates undergoing SPC or RVOTI from 2005-2017 were reviewed from the Congenital Cardiac Research Collaborative. The primary outcome was survival with successful complete repair (CR) by 18 months. A variety of secondary outcomes were assessed including overall survival, hospitalization-related comorbidities, and interstage reinterventions. Propensity score adjustment was utilized to compare treatment strategies. The cohort included 252 SPC (surgical shunt = 226, ductus arteriosus stent = 26) and 68 RVOTI (balloon pulmonary valvuloplasty = 48, RVOT stent = 11, RVOT patch = 9) patients. Genetic syndrome (29 [42.6%] v 75 [29.8%], p = 0.04), weight < 2.5 kg (28 [41.2%] v 68 [27.0%], p = 0.023), bilateral pulmonary artery Z-score < - 2 (19 [28.0%] v 36 [14.3%], p = 0.008), and pre-intervention antegrade flow (48 [70.6%] v 104 [41.3%], p < 0.001) were more common in RVOTI. Significant center differences were noted (p < 0.001). Adjusted survival to CR by 18 months (HR = 0.87, 95% CI = 0.63-1.21, p = 0.41) and overall survival (HR = 2.08, 95% CI = 0.93-4.65, p = 0.074) were similar. RVOTI had increased interstage reintervention (HR = 2.15, 95% CI = 1.36-3.99, p = 0.001). Total anesthesia (243 [213, 277] v 328 [308, 351] minutes, p < 0.001) and cardiopulmonary bypass times (117 [103, 132] v 151 [143, 160] minutes, p < 0.001) favored RVOTI. In this multicenter comparison of physiologic palliation strategies for sTOF, survival to successful CR and overall survival were similar; however, reintervention burden was significantly higher in RVOTI.

Interpreting Quality Improvement When Introducing New Technology: A Collaborative Experience in ASD Device Closures.

The objective of this study was to evaluate the impact of the regular introduction of new technologies into interventional cardiac catheterization procedures, in this case new atrial septal defect (ASD) closure devices, while conducting a multi-center collaborative initiative to reduce radiation usage during all procedures. Data were collected prospectively by 8 C3PO institutions between January 1, 2014 and December 31, 2017 for ASD device closure procedures in the cardiac catheterization lab during a quality improvement (QI) initiative aimed at reducing patient radiation exposure. Radiation exposure was measured in dose area product per body weight (µGy*m2/kg). Use of proposed practice change strategies at the beginning and end of the QI intervention period was assessed. Radiation exposure was summarized by institution and by initial type of device used for closure. This study included 602 ASD device closures. Without changes in patient characteristics, total fluoroscopy duration, or number of digital acquisitions, median radiation exposure decreased from 37 DAP/kg to 14 DAP/kg from 2014 to 2017. While all individual centers decreased overall median DAP/kg, the use of novel devices for ASD closure correlated with a temporary period of worsening institutional radiation exposure and increased fluoroscopy time. The introduction of new ASD closure devices resulted in increased radiation exposure during a QI project designed to reduce radiation exposure. Therefore, outcome assessment must be contextualized in QI projects, hospital evaluation, and public reporting, to acknowledge the expected variation during innovation and introduction of novel therapies.

Impact of Treatment Strategy on Outcomes in Isolated Pulmonary Artery of Ductal Origin.

Isolated pulmonary artery (PA) of ductal origin (IPADO) is a rare cardiac defect which requires surgical repair, with or without preceding palliation. We sought to determine the impact of treatment strategy on outcomes. Retrospective study of consecutive patients with IPADO that underwent staged or primary repair from 1/05 to 9/16 at 6 Congenital Cardiac Research Collaborative centers. Patients with single ventricle physiology, major aortopulmonary collaterals, or bilateral IPADO were excluded. Primary outcome was isolated PA z-score at late follow-up. Secondary outcomes included PA symmetry index (isolated:confluent PA diameter) and reintervention burden. Propensity score adjustment was used to account for baseline differences. Of 60 patients in the study cohort, 26 (43%) underwent staged and 34 (57%) primary repair. The staged and primary repair groups differed in weight at diagnosis and presence of other heart disease but not in baseline PA dimensions. Staged patients underwent ductal stent (n = 16) or surgical shunt (n = 10) placement followed by repair at 210 vs. 21 days in the primary repair group (p < 0.001). At median follow-up of 4.5 years post-repair, after adjustment, isolated PA z-score (- 0.74 [- 1.75, - 0.26] vs. - 1.95 [- 2.91, - 1.59], p = 0.012) and PA symmetry index (0.81 [0.49, 1.0] vs. 0.55 [0.48, 0.69], p = 0.042) significantly favored the staged repair group. Freedom from PA reintervention was not different between groups (adjusted HR 0.78 [0.41, 1.48]; p = 0.445). A staged approach to repair of IPADO is associated with superior isolated PA size and symmetry at late follow-up. Consideration should be given to initial palliation in IPADO patients, when feasible.

Data quality methods through remote source data verification auditing: results from the Congenital Cardiac Research Collaborative.

BACKGROUND: Multicentre research databases can provide insights into healthcare processes to improve outcomes and make practice recommendations for novel approaches. Effective audits can establish a framework for reporting research efforts, ensuring accurate reporting, and spearheading quality improvement. Although a variety of data auditing models and standards exist, barriers to effective auditing including costs, regulatory requirements, travel, and design complexity must be considered. MATERIALS AND METHODS: The Congenital Cardiac Research Collaborative conducted a virtual data training initiative and remote source data verification audit on a retrospective multicentre dataset. CCRC investigators across nine institutions were trained to extract and enter data into a robust dataset on patients with tetralogy of Fallot who required neonatal intervention. Centres provided de-identified source files for a randomised 10% patient sample audit. Key auditing variables, discrepancy types, and severity levels were analysed across two study groups, primary repair and staged repair. RESULTS: Of the total 572 study patients, data from 58 patients (31 staged repairs and 27 primary repairs) were source data verified. Amongst the 1790 variables audited, 45 discrepancies were discovered, resulting in an overall accuracy rate of 97.5%. High accuracy rates were consistent across all CCRC institutions ranging from 94.6% to 99.4% and were reported for both minor (1.5%) and major discrepancies type classifications (1.1%). CONCLUSION: Findings indicate that implementing a virtual multicentre training initiative and remote source data verification audit can identify data quality concerns and produce a reliable, high-quality dataset. Remote auditing capacity is especially important during the current COVID-19 pandemic.

Use of carotid and axillary artery approach for stenting the patent ductus arteriosus in infants with ductal-dependent pulmonary blood flow: A multicenter study from the congenital catheterization research collaborative.

BACKGROUND: Carotid artery (CA) and axillary artery (AA) access are increasingly used for transcatheter stenting of the patent ductus arteriosus (PDA), although reports are limited. METHODS: The Congenital Catheterization Research Collaborative (CCRC) reviewed multicenter data from infants who underwent PDA stenting via the CA or AA approach from 2008 to 2017, and compared outcomes to those of infants undergoing PDA stenting via the femoral artery (FA) approach. Post-procedure ultrasound (US) imaging was reviewed. RESULTS: Forty-nine infants underwent PDA stenting from the CA (n = 43) or AA (n = 6) approach, compared with 55 infants who underwent PDA stenting from the FA approach. The PDA was the sole pulmonary blood flow (PBF) source in 61% of infants in the CA/AA cohort, compared with 33% of the FA cohort (p < .01). Ductal tortuosity for CA/AA cohort was Type I (straight) in 10 (20%), Type II (one turn) in 17 (35%), and Type III (multiple turns) in 22 (45%) infants and reflected a greater degree of tortuosity when compared to the FA cohort (p < .01). In 17 infants with CA/AA approach, the "flip technique" was used, and was associated with shorter procedure times for highly tortuous PDA (Type III) patients. Rates of procedural complications were similar across access sites. Most common complications were access site injury (thrombus or bleeding) and stent malposition. No complications were specifically related to the "flip technique." CONCLUSIONS: Use of CA and AA approach for PDA stenting was found to be more commonly employed in sole source PBF and highly tortuous PDAs. Procedural modifications such as the "flip technique" may lead to shorter procedure times. CA and AA approaches are associated with a similar burden of procedural or late complications. Post-procedural surveillance of the CA and AA is suggested, given the incidence of vascular findings on US.

Echocardiographic versus angiographic measurement of the aortic valve annulus in children undergoing balloon aortic valvuloplasty: method affects outcomes.

OBJECTIVE: Operators are mindful of the balloon-to-aortic annulus ratio when performing balloon aortic valvuloplasty. The method of measurement of the aortic valve annulus has not been standardised. METHODS AND RESULTS: Patients who underwent aortic valvuloplasty at two paediatric centres between 2007 and 2014 were included. The valve annulus measured by echocardiography and angiography was used to calculate the balloon-to-aortic annulus ratio and measurements were compared. The primary endpoint was an increase in aortic insufficiency by ≥2 degrees. Ninety-eight patients with a median age at valvuloplasty of 2.1 months (Interquartile range (IQR): 0.2-105.5) were included. The angiographic-based annulus was 8.2 mm (IQR: 6.8-16.0), which was greater than echocardiogram-based annulus of 7.5 mm (IQR: 6.1-14.8) (p < 0.001). This corresponded to a significantly lower angiographic balloon-to-aortic annulus ratio of 0.9 (IQR: 0.9-1.0), compared to an echocardiographic ratio of 1.1 (IQR: 1.0-1.1) (p < 0.001). The degree of discrepancy in measured diameter increased with smaller valve diameters (p = 0.041) and in neonates (p = 0.044). There was significant disagreement between angiographic and echocardiographic balloon-to-aortic annulus ratio measures regarding "High" ratio of >1.2, with angiographic ratio flagging only 2/12 (16.7%) of patients flagged by echocardiographic ratio as "High" (p = 0.012). Patients who had an increase in the degree of aortic insufficiency post valvuloplasty, only 3 (5.5%) had angiographic ratio > 1.1, while 21 (38%) had echocardiographic ratio >1.1 (p < 0.001). Patients with resultant ≥ moderate insufficiency more often had an echocardiographic ratio of >1.1 than angiographic ratio of >1.1 There was no association between increase in balloon-to-aortic annulus ratio and gradient reduction. CONCLUSIONS: Angiographic measurement is associated with a greater measured aortic valve annulus and the development of aortic insufficiency. Operators should use caution when relying solely on angiographic measurement when performing balloon aortic valvuloplasty.

Correction: Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage.

BACKGROUND: Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group. METHODS: We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8+ and CD3+ densities were quantified by immunohistochemistry in tissue microarray (TMA) cores, and their association with clinical outcome analysed by Cox regression. We validated our results using publicly available gene expression data in a pooled analysis of 1375 CRCs from seven independent series. RESULTS: In QUASAR2, intratumoural CD8+ was a stronger predictor of CRC recurrence than CD3+ and showed similar discriminative ability to both markers in combination. Pooled multivariable analysis of both trials showed increasing CD8+ density was associated with reduced recurrence risk independent of confounders including DNA mismatch repair deficiency, POLE mutation and chromosomal instability (multivariable hazard ratio [HR] for each two-fold increase = 0.92, 95%CI = 0.87-0.97, P = 3.6 × 10-3). This association was not uniform across risk strata defined by tumour and nodal stage: absent in low-risk (pT3,N0) cases (HR = 1.03, 95%CI = 0.87-1.21, P = 0.75), modest in intermediate-risk (pT4,N0 or pT1-3,N1-2) cases (HR = 0.92, 95%CI = 0.86-1.0, P = 0.046) and strong in high-risk (pT4,N1-2) cases (HR = 0.87, 95%CI = 0.79-0.97, P = 9.4 × 10-3); PINTERACTION = 0.090. Analysis of tumour CD8A expression in the independent validation cohort revealed similar variation in prognostic value across risk strata (PINTERACTION = 0.048). CONCLUSIONS: The prognostic value of intratumoural CD8+ cell infiltration in stage II/III CRC varies across tumour and nodal risk strata.

Variability in radiation dose and image quality: A comparison across fluoroscopy-system vendors, generations of equipment and institutions.

OBJECTIVES: To evaluate differences in radiation dose and image quality across institutions, fluoroscope vendors and generations of fluoroscopes for pediatric cardiac catheterization. BACKGROUND: Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances in fluoroscopes, as well as increased focus on optimizing fluoroscope performance. There is currently little understanding of variability in the dose-image quality relationship across institutions, fluoroscope vendor and/or generation of equipment. METHODS: We evaluated latest generation fluoroscopes from Phillips, Siemens, GE, and Toshiba, and an older generation Phillips fluoroscope (release date 2003) at three different institutions. Radiation dose was measured using an anthropomorphic dose-assessment phantom with effective dose in mSv estimated from Monte Carlo simulations. Image quality phantom images were scored on a 12-point scale by three blinded reviewers. RESULTS: Fluoroscope effective doses ranged from 0.04 to 0.14 mSv/1,000 pulses for fluoroscopy with associated composite image quality scores ranging from 8.0 ± 0.6 to 10.4 ± 1.3. For cineangiography, effective doses ranged from 0.17 to 0.57 mSv/1,000 frames with image quality scores ranging from 10.1 ± 0.3 to 11.1 ± 0.3. There was modest correlation between effective dose and image quality (r = 0.67, P = 0.006). The older generation fluoroscope delivered consistently higher doses than the newer generation systems (2.3- to 3.5-fold higher for fluoroscopy; 1.1- to 3.4-fold higher for cineangiography) without appreciable differences in image quality. CONCLUSION: Technological advances have markedly improved fluoroscope performance. Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship and speculate that this reflects both equipment and institutional optimization practices.

Percutaneous Removal of Intravascular Pellet Following Penetrating Cardiac Trauma.

There is controversy regarding the management of projectile embolization, a rare complication of penetrating trauma. We present the case of a 5-year-old, 20 kg male with retrograde venous projectile embolization following traumatic injury with a pellet gun. The projectile was successfully removed utilizing a novel, percutaneous approach.

Abstract 12670: Variability in Radiation Dose and Image Quality: A Comparison Across Fluoroscopy-system Vendors and Generations of Equipment.

INTRODUCTION: Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances to reduce exposure during fluoroscopy. However there is currently little understanding of the dose-image quality (IQ) relationship between fluoroscopy vendors and across generations of equipment used for imaging during pediatric catheterization. METHODS: We evaluated latest generation fluoroscopy systems from Phillips, Siemens, GE and Toshiba, and an older generation Phillips system (2004 release). Fluoroscopy and cineangiography were performed on a tissue simulation anthropomorphic phantom using a standardized imaging approach. Phantom surface exposures were used for Monte Carlo simulations to calculate radiation effective dose, accounting for differences in beam parameters. We also imaged a fluoroscopy IQ phantom to assess contrast-detail and line-per-inch visualization. IQ images were scored by 3 blinded reviewers with scores averaged to produce a composite rating (scale 0-18). To assess the impact of imaging approach we then simulated a neonatal cardiac catheterization incorporating "typical" imaging protocols provided by institutions using the various systems. RESULTS: Effective doses and IQ scores are summarized in the table. Effective doses varied by >400% with the older generation system consistently delivering markedly higher doses. The associated figure summarizes dose and IQ for a simulated neonatal cardiac catheterization which accounts for measured doses as well as the reported institutional imaging parameters summarized in the figure legend. CONCLUSION: These data demonstrate substantial technological improvements in fluoroscopy equipment and may be useful to justify institutional "upgrades". Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship that reflects both equipment and imaging approach.

A note on statistical repeatability and study design for high-throughput assays.

Characterizing the technical precision of measurements is a necessary stage in the planning of experiments and in the formal sample size calculation for optimal design. Instruments that measure multiple analytes simultaneously, such as in high-throughput assays arising in biomedical research, pose particular challenges from a statistical perspective. The current most popular method for assessing precision of high-throughput assays is by scatterplotting data from technical replicates. Here, we question the statistical rationale of this approach from both an empirical and theoretical perspective, illustrating our discussion using four example data sets from different genomic platforms. We demonstrate that such scatterplots convey little statistical information of relevance and are potentially highly misleading. We present an alternative framework for assessing the precision of high-throughput assays and planning biomedical experiments. Our methods are based on repeatability-a long-established statistical quantity also known as the intraclass correlation coefficient. We provide guidance and software for estimation and visualization of repeatability of high-throughput assays, and for its incorporation into study design. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Late outcomes in children with Shone's complex: a single-centre, 20-year experience.

OBJECTIVE: Shone's syndrome is a complex consisting of mitral valve stenosis in addition to left ventricle outflow obstruction. There are a few studies evaluating the long-term outcomes in this population. We sought to determine the long-term outcomes in our paediatric population with Shone's syndrome and the factors associated with left heart growth. METHODS: All patients diagnosed with Shone's syndrome with biventricular circulation treated between 1978 and 2010 were reviewed. Baseline echocardiograms and data from catheterisations were also reviewed. Number of interventions (surgical+transcatheter), incidence of mitral valve replacement, and incidence of heart transplantation were tracked. Survival of the population and left heart structural growth were also reviewed. RESULTS: A total of 121 patients with Shone's syndrome presented at a median age of 28 days (0-17.3 years) and were followed-up for 7.2 years (0.01-35.5 years). These patients underwent 258 interventions during the study period, and the presence of coarctation was associated with repeat left heart interventions. The 10-year, transplant-free survival was 86%. Presence of pulmonary hypertension was associated with mortality. Left heart structural growth was seen for mitral and aortic valve annuli and left ventricular end-diastolic dimension over time. CONCLUSIONS: Shone's syndrome patients undergo a number of left heart interventions. Coarctation of the aorta is associated with an increased likelihood for repeat interventions. Survival appears to be more favourable than expected. Significant left heart growth will occur in the population. Pulmonary hypertension is associated with an increased risk of mortality.

Tissue Plasminogen Activator Use in Children: Bleeding Complications and Thrombus Resolution.

OBJECTIVE: To review our institutional experience with tissue plasminogen activator (tPA) to determine outcomes related to bleeding complications and thrombus resolution. STUDY DESIGN: We performed a retrospective review of all patients who received systemic tPA for thrombolysis. Data points included location of thrombus, initial and maximum tPA dose, and duration of tPA. The primary endpoint was bleeding complication. RESULTS: Between 2005 and 2014, 46 patients received systemic tPA for thrombolysis: 17 (37%) were patients with a primary cardiac diagnosis, there were 17 (37%) hematology/oncology patients, and 12 (26%) patients with noncardiac, nonhematology/oncology diagnoses. The indication for tPA was central venous thrombus (n = 23), pulmonary artery thrombus (n = 9), and cardiac or aortic thrombus (n = 14). Bleeding complications occurred in 15 patients (33%). Median initial tPA dose in the bleeding complication group was 0.10 mg/kg/h vs 0.03 mg/kg/h in the group without bleeding complication group (P = .01). Cardiac patients experienced more bleeding complications (P = .01). Multivariate analysis indicated that dose of tPA (P = .01) and diagnostic category (P < .01) were associated with bleeding complication. Complete thrombus resolution occurred in 21 patients, partial in 10 patients, and no resolution in 15 patients. Complete resolution of thrombus was not associated with diagnosis, thrombus location, tPA dose, or duration. CONCLUSIONS: Cardiac patients appear to be at highest risk of bleeding complication; bleeding complications were associated with higher doses of tPA, and cardiac patients were the cohort who received the highest doses of tPA. Higher tPA doses are associated with increased risk of bleeding complication but are not associated with successful thrombus resolution.

Adult onset global loss of the fto gene alters body composition and metabolism in the mouse.

The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.