Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy.

BACKGROUND: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. OBJECTIVES: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. METHODS: In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RESULTS: RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. CONCLUSIONS: RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

An Integrated Clinical and Genetic Prediction Model for Tacrolimus Levels in Pediatric Solid Organ Transplant Recipients.

BACKGROUND: There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study was to generate an integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT. METHODS: In a multicenter prospective observational cohort study (2015-2018), children <18 years old at their first SOT receiving tacrolimus as maintenance immunosuppression were included (455 as discovery cohort; 322 as validation cohort). Genotyping was performed using a genome-wide single nucleotide polymorphism (SNP) array and analyzed for association with tacrolimus trough levels during 1-y follow-up. RESULTS: Genome-wide association study adjusted for clinical factors identified 25 SNPs associated with tacrolimus levels; 8 were significant at a genome-wide level (P < 1.025 × 10-7). Nineteen SNPs were replicated in the validation cohort. After removing SNPs in strong linkage disequilibrium, 14 SNPs remained independently associated with tacrolimus levels. Both traditional and machine learning approaches selected organ type, age at transplant, rs776746, rs12333983, and rs12957142 SNPs as the top predictor variables for dose-adjusted 36- to 48-h posttacrolimus initiation (T1) levels. There was a significant interaction between age and organ type with rs776476*1 SNP (P < 0.05). The combined clinical and genetic model had lower prediction error and explained 30% of the variation in dose-adjusted T1 levels compared with 18% by the clinical and 12% by the genetic only model. CONCLUSIONS: Our study highlights the importance of incorporating age, organ type, and genotype in predicting tacrolimus levels and lays the groundwork for developing an individualized age and organ-specific genotype-guided tacrolimus dosing algorithm.

Genetic Diagnosis and the Severity of Cardiovascular Phenotype in Patients With Elastin Arteriopathy.

BACKGROUND: Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (ELN) causes Williams-Beuren syndrome (WBS), while single nucleotide variants in ELN cause nonsyndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and nonsyndromic SVAS. METHODS: Patients (81 WBS, 42 nonsyndromic SVAS) with cardiovascular disease were included in this retrospective single center study. Freedom from surgical and catheter interventions and reinterventions was compared. Vascular tissue from 8 patients and 6 controls was analyzed for arterial wall architecture. RESULTS: Patients with nonsyndromic SVAS presented at a younger age (median 0.3 [0.4-0.7] years) compared with patients with WBS (1.3 [0.2-3.0] years) and had lower freedom from surgical/catheter interventions compared with patients with WBS, with median event-free survival 1.1 (0.3-5.9) versus 4.7 (2.4-13.3) years, respectively (hazard ratio, 1.62 [95% CI, 1.02-2.56]; P=0.04). Patients with nonsyndromic SVAS also had a lower freedom from reinterventions (P=0.054 by log-rank test). This was related in part to a higher frequency of primary and reinterventions for concomitant valvar aortic stenosis. Histology revealed abnormal intimal and medial thickening, disorganized and fragmented elastic fibers, reduced smooth muscle calponin expression, and increased macrophage marker, CD68, expression in the arterial walls in patients with WBS and nonsyndromic SVAS compared with controls. CONCLUSIONS: Patients with nonsyndromic SVAS require early and more frequent vascular and valvular interventions and reinterventions, in particular for concomitant valvar aortic stenosis compared with patients with WBS. This provides important prognostic information to guide counseling of affected families with cardiovascular disease and may guide primary intervention strategies based on predicted risk of restenosis.

Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy (POSITIVE Study): The Collaboration and Design of a National Transplant Precision Medicine Program.

BACKGROUND: Despite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults. METHODS: In this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults. RESULTS: From 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion. CONCLUSIONS: The design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation.

BACKGROUND: Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied. OBJECTIVE: To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations. SETTING: Single hospital-based transplant center. METHODS: This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6 years) and randomized (2:1) after transplant to receive genotype-guided (n = 35) or standard (n = 18) starting dose of tacrolimus for 36-48 hours and were followed for 30 days. RESULTS: Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6) days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P = 0.049), and had fewer out-of-range concentrations [OR (95% CI) = 0.60 (0.44, 0.83), P = 0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups. CONCLUSIONS: CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations.

Patient satisfaction and health-related quality of life after autologous tissue breast reconstruction: a prospective analysis of early postoperative outcomes.

BACKGROUND: For this study, the authors evaluated early psychosocial adjustments and health-related quality-of-life changes after breast reconstruction. METHODS: All consecutive patients who underwent breast reconstruction between June 2009 and November 2010 were asked to complete the BREAST-Q, Hospital Anxiety and Depression Scale (HADS), and Impact of Event Scale (IES) questionnaires before surgery and at 3 weeks and 3 months after surgery. A repeated-measures design was used to compare scores between baseline and postoperative time points. RESULTS: Fifty-one of 55 women completed the questionnaires (response rate, 93%). BREAST-Q subscale scores (breast, sexual well being, and psychosocial well being) improved significantly (P < .05) postoperatively. The other subscale scores related to physical well being of the chest and abdomen dropped significantly 3 weeks after reconstruction; and, by 3 months after reconstruction, both scores improved significantly (P < .05). Large effect sizes for improvements in satisfaction, psychosocial well being, and sexual well being were observed (1.88, 1.2, and 1.31, respectively); whereas deterioration in the effect size for abdominal donor site was reported (-1.56). After adjusting for postoperative complications, there were statistically significant changes in BREAST-Q subscale scores. Changes observed on the HADS and IES provided external validation of the findings obtained on the BREAST-Q. CONCLUSIONS: The current results suggested that the gains in breast satisfaction, psychosocial well being, and sexual well being after patients undergo either free muscle-sparing transverse rectus abdominis myocutaneous flap reconstruction or deep inferior epigastric artery flap reconstruction are statistically significant and clinically meaningful to the patient as early as 3 weeks after surgery. However, these gains are accompanied by significant deterioration in physical well being of the abdominal donor site.

The use of the 'rollie' in New Zealand: preference for loose tobacco among an ethnically diverse low socioeconomic urban population.

AIM: To examine the prevalence of and reasons for smoking roll-your-own (RYO) cigarettes in a population of South Auckland adults. METHOD: Cross-sectional survey of the parents of 2,973 children at four South Auckland Intermediate Schools in 2007-2009. RESULT: Just over a quarter (813; 27%) of parents were smokers. Most (82%) were Maori or Pacific peoples (47% and 34% respectively) of whom 47% smoked only factory-made (FM) and 38% smoked only RYO cigarettes. Exclusive RYO smoking was more common among European (53%) than Maori (40%), Pacific (38%) and Asian ethnic groups (23%). The most common reasons for preferring RYO over FM cigarettes were lower cost (50%), lasting longer (42%), and taste (8%). A few chose RYO because they perceived them to be less harmful (5%). CONCLUSION: Reducing the cost benefit of RYO should lessen the potential use of RYOs as an alternative to quitting. Health education campaigns are needed to counter incorrect beliefs surrounding RYO. Such programmes should include awareness in schools, churches and Pacific communities.

Driving kids to smoke? Children's reported exposure to smoke in cars and early smoking initiation.

The health risks associated with second hand smoke (SHS) are well-known. However, little is known about exposure to SHS in cars and risk of smoking uptake. This paper investigates the association between pre-adolescents reported exposure to smoking in cars and prevalence of early stage smoking activity. Data from Keeping Kids Smokefree baseline surveys of students were used to investigate smoking status and reported exposure to smoking in cars. Log binomial regression analyses were used to investigate if reported exposure to SHS in cars was associated with smoking prevalence. 83% of 5676 students invited took part. After controlling for all variables reported exposure to smoking in cars and homes were significantly associated with increased risk of initiated smoking (RR 1.87, 95% CI 1.43-2.44, and RR 1.5, 95% CI 1.13-1.97, respectively). Exposure to smoking in cars was substantially and significantly associated with risk of current smoking (RR 3.21, 95% CI 1.45-7.08). Early smoking uptake is associated with students' reported exposure to smoking in cars which confirms the importance of protecting children from SHS. Smoking in cars is under parental control and therefore modifiable. Moreover, children's reports of SHlS exposure offer a simple way of identifying families who can be targeted for tobacco control interventions.

Impact of national smokefree environments laws on teachers, schools and early childhood centres.

ISSUE ADDRESSED: New Zealand's (NZ) smokefree legislation, implemented on 1 January 2004, requires that all school and early childhood centre buildings and grounds are 100% smokefree; one aim being to prevent young people being influenced by seeing people (including teachers) smoke there. This study, conducted in 2008, investigated teachers'smoking behaviour and perceived adherence to the legislation. METHODS: A national NZ cross-sectional survey of 2,004 teachers (oversampling Maori), who were randomly selected from the electoral roll of registered voters and sent postal invitations to complete an anonymous survey. RESULTS: The response rate was 70%. Current smokers numbered 7%, and proportionately more Maori and Pacific Island teachers (12% each) smoked than European/Other teachers (7%). Of current smokers, 37% smoked non-daily. Smokers smoked less on work than non-work days. Introducing smokefree legislation was associated with teachers changing when they smoked, cutting down, quitting or trying to quit. Perceived compliance with the legislation was high, although 30% of teachers reported seeing staff smoking. Proportionately, significantly more teachers from low than from high socioeconomic schools perceived poor compliance and staff visibly smoking. CONCLUSIONS: Smokefree legislation affects people's smoking behaviour. Smoking in NZ is becoming confined to population subgroups defined by socioeconomic status and ethnicity. Our findings argue for supporting cessation among those who work with children and young people, and for targeting support at school communities in areas of low socioeconomic status or with large populations of Maori or Pacific peoples.

Smoking is rank! But, not as rank as other drugs and bullying say New Zealand parents of pre-adolescent children.

ISSUE ADDRESSED: Despite the established risks associated with smoking, 21% of New Zealand adults smoke. Prevalence among Maori (indigenous) and Pacific Island New Zealanders is disproportionately high. Prevention of smoking initiation is a key component of tobacco control. Keeping Kids Smokefree--a quasi-experimental trial--aimed to do this by changing parental smoking behaviour and attitudes. However, little is known about parents' attitudes to smoking in comparison with other concerns. METHOD: Parents of 4,144 children attending five urban schools in a high smoking prevalence population in Auckland, New Zealand, were asked to rank seven concerns on a paper-based questionnaire, including smoking, alcohol and bullying, from most to least serious. RESULTS: Methamphetamine and other illicit 'hard' drugs were ranked as most serious followed by marijuana smoking, alcohol drinking, bullying, cigarette smoking, sex and obesity. Never smokers ranked cigarette smoking as more serious than current or ex-smokers. CONCLUSION: Parents' under-estimation of the serious nature of tobacco smoking relative to other drugs could partly explain low participation rates in parent-focused smoking initiation prevention programs.