3-generation family medical histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism.

Background: Family histories of different mental and non-mental conditions have often been associated with autism spectrum disorder (ASD) but the restricted scope of conditions and family members that have been investigated limits etiologic understanding. We aimed to perform a comprehensive assessment of ASD associations with 3-generation family histories of 90 mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. The assessment comprised separate estimates of association with ASD overall; separate estimates by sex and intellectual disability (ID) status; as well as separate estimates of the co-occurrence of each of the 90 disorders in autistic persons. Additionally, we aimed to provide interactive catalogues of results to facilitate results visualization and further hypothesis-generation. Methods: We conducted a population-based, registry cohort study comprised of all live births in Denmark, 1980-2012, of Denmark-born parents, and with birth registry information (1,697,231 births), and their 3-generation family member types (20 types). All cohort members were followed from birth through April 10, 2017 for an ASD diagnosis. All participants (cohort members and each family member) were followed from birth through April 10, 2017 for each of 90 diagnoses, emigration or death. Adjusted hazard ratios (aHR) were estimated for ASD overall; by sex; or accounting for ID via separate Cox regression models for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person. aHRs were also calculated for sex-specific co-occurrence of each disorder, for ASD overall and considering ID. A catalogue of all results is displayed via interactive heat maps here: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries of results are here: https://public.tableau.com/views/ASDPlots_16918786403110/e-Figure5. Results: Increased aHRs for ASD (26,840 cases; 1.6% of births) were observed for almost all individual mental disorder-family member type combinations yet for fewer non-mental disorder-family member type combinations. aHRs declined with diminishing degree of relatedness between the index person and family member for some disorders, especially mental disorders. Variation in aHR magnitude by family member sex (e.g., higher maternal than paternal aHRs) or side of the family (e.g., higher maternal versus paternal half sibling aHRs) was more evident among non-mental than mental disorders. Co-occurring ID in the family member or the index person impacted aHR variation. Conclusion: Our approach revealed considerable breadth and variation in magnitude of familial health history associations with ASD by type of condition, sex of the affected family member, side of the family, sex of the index person, and ID status which is indicative of diverse genetic, familial, and non-genetic ASD etiologic pathways. More careful attention to identifying sources of autism likelihood encompassed in family medical history, in addition to genetics, may accelerate understanding of factors underlying neurodiversity.

The Familial Risk of Autism Spectrum Disorder with and without Intellectual Disability.

Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies.

Correlation of Echocardiogram and Exercise Test Data in Children with Aortic Stenosis.

Previous pediatric exercise test criteria for aortic stenosis severity were based on cardiac catheterization assessment, whereas current criteria are based on echocardiographic valve gradients. We sought to correlate exercise test criteria with echocardiographic assessment of severity. We report 65 studies, 51 patients (mean age of 13 ± 4 years; 75% males), with aortic stenosis (AS) who had a maximal exercise test between 2005 and 2016. We defined three groups based on resting mean Doppler gradient across their aortic valve: severe AS (n = 10; gradient of ≥ 40 mmHg), moderate AS (n = 20; gradient 25-39 mmHg), and mild AS (n = 35; gradient ≤ 24 mmHg). We studied symptoms (chest pain) during exercise, resting electrocardiogram changes (left ventricular hypertrophy [LVH]), complex arrhythmias during exercise, change in exercise systolic blood pressure (SBP; delta SBP = peak SBP-resting SBP), exercise duration, work, echocardiogram parameters (LVH), and ST-T wave changes with exercise. Additionally, we compared work and delta SBP during exercise with 117 control males and females without heart disease. Severe AS patients have statistically significant differences when compared with mild AS in ST-T wave depression during exercise, LVH on resting electrocardiogram, and echocardiogram. There was a significant difference in delta SBP between severe AS and normal controls (delta SBP 21.6 vs. 46.2 mmHg), and between moderate AS and normal controls (delta SBP 32 vs. 46.2 mmHg). There were no significant complications during maximal exercise testing. Children with echocardiographic severe and moderate AS have exercise testing abnormalities. Exercise test criteria for severity of AS were validated for echocardiographic criteria for AS severity.

Standardization of a Continuous Ramp Ergometer Protocol for Clinical Exercise Testing in Children.

Developing a standardized protocol for pediatric exercise laboratories is challenging. Our objective was to report normal pediatric values for a continuous non-steady state cycle ergometer ramp protocol to achieve 8-10 min of exercise based on sex and weight. One hundred seventeen patients (117) [mean age 13 ± 2.8 years, range 7-18 years (51% male)] referred for chest pain with normal cardiac evaluation underwent cardiopulmonary testing on a cycle ergometer. Patients entered one of the four continuous ramp protocols (10, 15, 20, and 25 W/min ramp) to achieve an expected peak workload of 3 W/kg at an increase of 0.3 to 0.35 W/kg/min. Exercise test outcomes measured included duration, peak heart rate, work, respiratory exchange ratio, peak oxygen consumption, peak blood pressure, and ventilatory anaerobic threshold. An exercise duration of 8-10 min was achieved in a majority of the study population; however, interactions with age (older, longer duration) and sex (males, longer duration) were present. Using our algorithm (0.3-0.35 W/kg × weight), we demonstrated four non-steady state ramp bike ergometer protocols (10, 15, 20, and 25 W/min) that can be applied to males and females of different ages and weights to achieve an exercise duration of 8-10 min.

Family History of Mental and Neurological Disorders and Risk of Autism.

Importance: Familial aggregation of mental and neurological disorders is often observed in autism spectrum disorders (ASD), but reports have generally focused on single disorders and are limited to first-degree relatives. Objectives: To examine family history of mental and neurological disorders among first- to fourth-degree relatives and risk of ASD with and without intellectual disability (ID) in index persons. Design, Setting, and Participants: In this population-based cohort study, 567 436 index persons were identified from the Stockholm Youth Cohort, an ongoing longitudinal register-linkage cohort study of the total population aged 0 to 17 years residing in Stockholm County, Sweden. Index persons were nonadopted singleton births born between 1984 and 2009 who were at least 2 years of age at the end of follow-up on December 31, 2011, had resided in Stockholm County for at least 2 years since birth, and could be linked to both biological parents. Data analysis was conducted from May 2017 to December 2018. Exposure: Mental and neurological diagnoses of relatives of the index persons. Main Outcomes and Measures: Diagnosis of ASD, with or without co-occurring ID, in the index persons. Results: The cohort included 567 436 index persons (291 191 [51.3%] male; mean [SD] age at the end of follow-up, 14.3 [7.5] years). The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively. Positive family history of mental and neurological disorders was associated with higher odds of ASD in index persons; 6895 (63.1%) of index persons with ASD had a parent with history of mental and/or neurological disorders, compared with 252 454 (45.4%) of index persons without ASD. Family history of multiple disorders was associated with higher odds of ASD in index persons, including history of ASD (odds ratio among first-degree relatives for ASD with and without ID: 14.2, 9.0), intellectual disability (7.6, 2.3), attention-deficit/hyperactivity disorder (3.3, 4.7), obsessive compulsive disorder (1.9, 2.1), schizophrenia and other nonaffective psychotic disorders (2.1, 1.8), depression (1.4, 2.0), bipolar disorder (1.4, 2.2), personality disorder (2.1, 2.6), cerebral palsy (2.2, 1.5), and epilepsy (2.0, 1.3). The more closely related the affected family member was, the higher the odds was of ASD for the index person. ASD without intellectual disability was associated with more disorders compared to ASD with intellectual disability. ASD with intellectual disability exhibited a weaker familial association with other mental disorder diagnoses but a stronger familial association with some neurological diagnoses as compared to ASD without intellectual disability. Conclusions and Relevance: This study suggests that family history of mental and neurological disorders is associated with increased risk of ASD. The familial component of ASD etiology may differ by presence or absence of co-occurring ID.

A large-volume academic center retrospective audit of the temporal evolution of immediate breast reconstruction protocols and the effect on breast prosthetic infection.

BACKGROUND: Complications of tissue expanders (TEs) in breast reconstruction are challenging. We sought to identify TE infection risks and acellular dermal matrix (ADM) and infection control protocol impacts on infection in a longitudinal study. METHODS: We retrospectively analyzed TE/implant reconstructions in 2004 (no ADM), 2009 (TE and ADM), 2013 (TE, ADM, and infection control protocol), and 2015 (TE, ADM, and infection control protocol). We assessed demographic, disease, and operative factors and analyzed rates of seroma, hematoma, skin necrosis, and infection. Statistical analysis, including simple and multivariable logistic regression, was performed using Stata v13.1. RESULTS: 478 TEs were placed in 324 women, with a 30% overall patient complication rate (23% of breasts). A total of 14% of TEs became infected. Although unadjusted analysis showed no ADM and infection association (p = 0.269), multivariable logistic regression showed a significant association with more infections (OR: 3.21; 95% CI: 1.13-9.313; p = 0.029). The infection control protocol decreased infections by 28% (16% in 2009 vs 11% in 2013); however, this did not achieve statistical significance (unadjusted p = 0.192, adjusted p = 0.156). Seroma (p < 0.001), older age (p = 0.040), larger mastectomy volume (p = 0.001), smoking (p = 0.037), BMI (p < 0.001), vascular disorders (p = 0.007), and hypertension (p < 0.001) significantly increased infections. CONCLUSIONS: Identifiable risks exist in TE/implant breast reconstruction. ADM infection risk may mitigate some potential benefits. Anti-infection protocols may reduce infections, and further investigation may reveal the most effective prophylactic strategies. Absence of major changes in complications over time supports validity of studies examining large numbers of despite evolution of techniques.

Feasibility of Using a Commercial Fitness Tracker as an Adjunct to Family-Based Weight Management Treatment: Pilot Randomized Trial.

BACKGROUND: Fitness trackers can engage users through automated self-monitoring of physical activity. Studies evaluating the utility of fitness trackers are limited among adolescents, who are often difficult to engage in weight management treatment and are heavy technology users. OBJECTIVE: We conducted a pilot randomized trial to describe the impact of providing adolescents and caregivers with fitness trackers as an adjunct to treatment in a tertiary care weight management clinic on adolescent fitness tracker satisfaction, fitness tracker utilization patterns, and physical activity levels. METHODS: Adolescents were randomized to 1 of 2 groups (adolescent or dyad) at their initial weight management clinic visit. Adolescents received a fitness tracker and counseling around activity data in addition to standard treatment. A caregiver of adolescents in the dyad group also received a fitness tracker. Satisfaction with the fitness tracker, fitness tracker utilization patterns, and physical activity patterns were evaluated over 3 months. RESULTS: A total of 88 adolescents were enrolled, with 69% (61/88) being female, 36% (32/88) black, 23% (20/88) Hispanic, and 63% (55/88) with severe obesity. Most adolescents reported that the fitness tracker was helping them meet their healthy lifestyle goals (69%) and be more motivated to achieve a healthy weight (66%). Despite this, 68% discontinued use of the fitness tracker by the end of the study. There were no significant differences between the adolescent and the dyad group in outcomes, but adolescents in the dyad group were 12.2 times more likely to discontinue using their fitness tracker if their caregiver also discontinued use of their fitness tracker (95% CI 2.4-61.6). Compared with adolescents who discontinued use of the fitness tracker during the study, adolescents who continued to use the fitness tracker recorded a higher number of daily steps in months 2 and 3 of the study (mean 5760 vs 4148 in month 2, P=.005, and mean 5942 vs 3487 in month 3, P=.002). CONCLUSIONS: Despite high levels of satisfaction with the fitness trackers, fitness tracker discontinuation rates were high, especially among adolescents whose caregivers also discontinued use of their fitness tracker. More studies are needed to determine how to sustain the use of fitness trackers among adolescents with obesity and engage caregivers in adolescent weight management interventions.

Addressing Human Papillomavirus Prevention During Pediatric Acute Sexual Assault Care.

BACKGROUND/OBJECTIVES: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Pediatric sexual assault (SA) victims are a special population eligible for HPV vaccination at the age of 9 years. National clinical practice guidelines advise clinicians to address HPV during emergency department (ED)-based SA care and at follow-up. At our institution, addressing HPV among suspected SA victims was highly variable, and HPV counseling was subsequently recommended on an ED-based acute SA clinical pathway as standard care. The aim of this study was to determine the proportion of age-eligible SA victims who received HPV counseling, determine victim characteristics associated with addressing HPV during SA care, and identify barriers to addressing HPV in the ED. METHODS: This study used a retrospective chart review of 448 pediatric SA victims presenting to the ED for acute postassault care. RESULTS: HPV was discussed in 10 of 56 (18%) and 37 of 49 (76%) cases in the control versus intervention groups, respectively. To verify vaccination status, caregiver recall was relied upon for 32 of 56 patients in the control group (57%) and 24 of 49 patients in the intervention group (48.9%). Factors associated with failure to discuss HPV during postassault care were younger age at encounter (OR = 0.78, 95% CI [0.67, 0.90], p < 0.001), verbal report of vaccination status verification (OR = 2.98, 95% CI [1.51, 6.01]), and male gender of the victim (OR = 3.35, 95% CI [1.20, 11.94]). CONCLUSIONS: Significant barriers to addressing HPV in the ED setting exist, most significantly reliance on caregiver recall to guide vaccination administration, raising concern for overvaccination and undervaccination.

Survival differences in childhood and young adult acute myeloid leukemia: A cross-national study using US and England data.

BACKGROUND: Acute myeloid leukemia (AML) is a serious disease with complex etiology and marked variation in survival. Known prognostic factors include AML subtypes, age at diagnosis and sex. However, survival outcomes may vary across healthcare systems. In this study, we evaluated the survival patterns in individuals diagnosed with AML at ages 0-24 years in the US and England between prognostic features and across countries. METHODS: We obtained data on 4387 and 2194 subjects from the US Surveillance Epidemiology and End Result registries and UK National Cancer Data Repository. Subjects were diagnosed and followed in 1995-2014. Kaplan-Meier curve and stratified Cox proportional hazards regression were used in the analysis. RESULTS: Overall risk of mortality was 23% lower in English patients compared to that in the US patients (adjusted hazard ratio (aHR), 95% confidence Interval (CI): 0.77, 0.71-0.84). Survival difference of similar extent was observed in subgroups of sex and age at diagnosis. However, mortality risks between two countries varied substantially across AML subtypes, especially in AML inv(16) (1.81, 0.61-5.34), AML with minimal differentiation (0.54, 0.25-1.17), AML without maturation (0.38, 0.20-0.74) and AML with maturation (0.52, 0.31-0.86). CONCLUSIONS: Similar to the population trend, mortality risk across sex, age at diagnosis, and most AML subtypes was lower in England. Survival outcome for AML with and without maturation in England was better than the population trend, while that for AML inv(16) was worse. Our findings suggest that future etiologic and policy research may uncover the underlying mechanisms and contribute to closing these morality gaps.

Prevalence of Autism Spectrum Disorders with and without Intellectual Disability by Gestational Age at Birth in the Stockholm Youth Cohort: a Register Linkage Study.

BACKGROUND: Preterm birth has been linked to increased risk of autism spectrum disorders (ASD), but how this risk changes with gestational age at birth has not been well characterised, especially with regard to co-occurring intellectual disability (ID). METHODS: Register-based cohort study of singleton births in 1984-2007 in Stockholm County, Sweden (N total: 480 728; n ASD: 10 025). We assessed overall and sex-specific, gestational week-specific prevalence estimates and risk ratios of ASD with and without ID. RESULTS: Preterm and postterm births were associated with elevated risk of ASD, and the relationship between gestational age at birth and ASD with and without ID differed in males and females. Risk of ASD without ID was higher in preterm births among both sexes and decreased continuously with increasing length of gestation. Risk of ASD with ID was higher in both preterm and postterm births among both sexes, with postterm birth in females being more highly associated with ASD with ID than that in males. CONCLUSIONS: The relationship between gestational age at birth and ASD differs by the presence/absence of co-occurring ID and fetal sex. Both preterm and postterm birth are associated with increased risk of ASD. Risk of ASD is not constant within conventionally defined gestational age at birth periods. Further research on mechanism underlying these associations is needed.