Economic Outcomes of a Precision Medicine Blood Test To Assess Obstructive Coronary Artery Disease: Results from the PRESET Registry.

PURPOSE: The evaluation of obstructive coronary artery disease (CAD) is inefficient and costly. Previous studies of an age/sex/gene expression score (ASGES) in this diagnostic workup have shown a 96% negative predictive value, as well as an 85% decreased likelihood of cardiac referral among low-score outpatients at 45 days. The objective was to explore the one-year cost implications of ASGES use among symptomatic outpatients. DESIGN: A prospective PRESET Registry (NCT01677156) enrolled stable, nonacute adult patients presenting with symptoms suggestive of obstructive CAD at 21 U.S. primary care practices. METHODOLOGY: Demographics, clinical factors, and ASGES (defined as low <=15 or elevated >15), as well as management plans post-ASGES, were collected. The economic endpoint analysis was based on the cost of cardiovascular-related tests, procedures, office visits, emergency room visits, and hospitalizations during one year after testing. RESULTS: The analysis included 566 patients, 51% of whom were women and the median age was 56. Forty-five percent had a low ASGES. The mean cost of cardiovascular care for patients in the year following ASGES was $1,647 for patients with a low ASGES versus $2,709 for those with an elevated score (39% reduction, P=.03 by Wilcoxon rank test). This relationship remained after multivariate analysis that adjusted for patient demographics and clinical covariates (P<.001). CONCLUSION: The ASGES helped identify patients with low current likelihood of obstructive CAD. These patients had lower costs of cardiovascular care during one year of follow-up. Early reductions in cardiac referrals at 45 days among these patients persisted at one year.

Navigating parental disagreement: ethical analysis and a proposed approach.

Shared decision-making in pediatrics can be problematic when disagreements arise. The impermissible-permissible-obligatory (I-P-O) framework helps define the limits of parental authority when clinicians disagree with parents. There is little guidance in the literature, however, on making critical clinical decisions when parents disagree with each other. We use a clinical case involving parental disagreement over resuscitation at borderline gestational age to provide context for an analysis of several potential approaches based on established ethical principles of pediatric decision-making. We identify four potential options for delivery room care: (1) Defer to the pregnant parent; (2) withhold resuscitation unless both parents agree to it; (3) attempt resuscitation if either parent requests it; (4) decide about resuscitation using a framework of advisability. The merits and flaws of each approach are discussed. We propose an expansion of the I-P-O framework that uses consideration of clinical details, an assessment of the patient's best interest, and parental values to determine clinical advisability to guide decision-making in the setting of parental discordance.

Ethical and Legal Perspectives on the Treatment of Hypoxic Ischemic Encephalopathy in the Newborn.

Hypoxic ischemic encephalopathy (HIE) in neonates can cause severe, life-long functional impairments or death. Treatment of these neonates can involve ethically challenging questions about if, when, and how it may be appropriate to limit life-sustaining medical therapy. Further, parents whose infants suffer severe neurologic damage may seek recourse in the form of a medical malpractice lawsuit. This study uses several hypothetical cases to highlight important ethical and legal considerations in the care of infants with HIE.

Diabetes in young people in the Top End of the Northern Territory.

AIM: There is an increasing prevalence and burden of diabetes in young people, particularly Indigenous Australians. There have been no previous reports of the prevalence or burden of diabetes in young people in the Top End of the Northern Territory, a region of many risk factors for diabetes. METHODS: This is a retrospective study of cases of diabetes in children and adults aged less than 25 years who were seen at Royal Darwin Hospital as inpatients or outpatients between 2007 and 2011. RESULTS: From a population base of approximately 75 000 young people living north of Tenant Creek, there were 70 young people with type 1 diabetes (12 Aboriginal and/or Torres Strait Islander Australians) and 37 young people with type 2 diabetes (31 Aboriginal or Torres Strait Islander Australians). The median body mass index of those with type 2 diabetes was 28 kg/m(2) , and only 29% had a body mass index >30 kg/m(2) . Overall, glycaemic control was poor. CONCLUSIONS: Rates of diabetes in young people in the Top End appear high. Case ascertainment and data collection were difficult for this study, highlighting the need for better database and systems for diabetes management.

Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children: A Randomized Clinical Trial.

Importance: Obstructive sleep-disordered breathing (SDB) in children is characterized by snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy children and is associated with significant morbidity. Evidence from small clinical trials suggests that intranasal corticosteroids improve SDB as measured by polysomnography; however, the effect on symptoms and quality of life is unclear. Objective: To determine whether intranasal mometasone furoate is more effective than intranasal saline for improving symptoms and quality of life in children with SDB. Design, Setting, and Participants: The MIST trial was a multicenter, randomized, double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for significant SDB symptoms were included; exclusions were previous adenotonsillectomy, body mass index greater than the 97th percentile, and severe SDB. Randomization was stratified by site, and data were analyzed on an intention-to-treat basis from October 28, 2020, to September 25, 2022. Interventions: Participants were randomly assigned to receive mometasone furoate, 50 µg, or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles. Main Outcomes and Measures: The primary outcome was resolution of significant SDB symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of symptoms using the SDB Score. Results: A total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals [53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants (41%) in the saline group (risk difference, 4%; 95% CI, -8% to 16%; P = .51) with 26 participants lost to follow-up and missing values managed by multiple imputation. The main adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting 12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%) in the saline group. Conclusions and Relevance: Results of this randomized clinical trial suggest that there was no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. The results suggest that almost one-half of children with SDB could be initially managed in the primary care setting and may not require referral to specialist services, as is currently recommended. Trial Registration: Australian New Zealand Clinical Trials Registry: ANZCTRN12618000448246.

Contamination rates of different urine collection methods for the diagnosis of urinary tract infections in young children: an observational cohort study.

AIMS: The optimal method for diagnostic collection of urine in children is unclear. National Institute of Health and Clinical Excellence recommend specimens taken by clean catch urine (CCU) for identification of urinary tract infection (UTI). We investigated contamination rates for CCU, suprapubic aspiration (SPA), catheter specimen urine (CSU) and bag specimen urine (BSU) collections. METHOD: Retrospective observational cohort study with review of microbiology data and medical records at a large tertiary children's hospital. We reviewed urine culture growth from consecutive first urine specimens of children aged <2 years, over a 3-month period in 2008. Patient demographics, collection method, location (emergency department, inpatient ward), culture growth, history of UTI, urogenital tract abnormality and antibiotic use were assessed. Contamination rates for collection methods were compared using logistic regression. RESULTS: Urine culture specimens of 599 children (mean age 7.0 months, 54% male) were included. There were 34% CCU, 16% CSU, 14% SPA, 2% BSU and 34% with unknown sample method. Contamination rates were 26% in CCU, 12% in CSU (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.8) and 1% in SPA (OR 0.03 95% CI 0.0-0.3). Concurrent antibiotics use was associated with a lower contamination rate. Contamination rates were not associated with age, sex, location, history of UTI or urogenital abnormalities. CONCLUSION: Contamination rates in CCU are much higher than in CSU and SPA samples. Ideally, SPA should be used for microbiological assessment of urine in young children. Collection procedures need to be optimised if CCU is used.

Factors Considered by Interprofessional Team for Treatment Decision in Hip Fracture with Dementia.

OBJECTIVES: Patients with dementia are at high risk for hip fractures and often have poor outcomes when a fracture is sustained. Despite this poor prognosis, little data are available on what factors should be prioritized to guide surgical decision making in these cases. We aimed to understand the decision-making process for older dementia patients hospitalized after hip fractures. DESIGN: We performed a qualitative analysis of in-depth elite interviews conducted with a clinical care team involved in management of patients with dementia after hospitalization for hip fractures. SETTING: Interviews were conducted with an interprofessional team involved in the care of patients with dementia after being hospitalized for hip fractures. PARTICIPANTS: Interviewees included nine orthopaedic surgeons, three hospitalists, three geriatricians, five nurses, three occupational therapists, three physical therapists, and two clinical ethicists. MEASUREMENTS: Verbatim transcripts of the interviews were analyzed and coded using QSR International's NVivo 10 qualitative database management software. RESULTS: The three main themes that most interviewees discussed were pain control, functional status, and medical comorbidities. Interviewees brought up many factors related to restoring functional status including baseline functional status, rehabilitation potential, social support, and the importance of mobility. Dementia and its impact on rehabilitation potential were mentioned by all geriatricians. CONCLUSION: Although frailty, prognosis, and life expectancy were largely absent from the responses, the emphasis on dementia, advanced directives, and involving family or caregivers by the three geriatricians indicates the importance of including geriatricians in the decision-making team for these patients.

Epigenetic Signatures of Salivary Gland Inflammation in Sjögren's Syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is a complex multisystem autoimmune disease that results in progressive destruction of the exocrine glands. The purpose of this study was to characterize epigenetic changes in affected gland tissue and describe the relationship of these changes to known inflammatory processes. METHODS: A genome-wide DNA methylation study was performed on human labial salivary gland (LSG) biopsy samples obtained from 28 female members of the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. Gland tissue was methylotyped using the Illumina HumanMethylation450 BeadChip platform, followed by rigorous probe-filtering and data-normalization procedures. RESULTS: A genome-wide case-control study of 26 of the 28 subjects revealed 7,820 differentially methylated positions (DMPs) associated with disease status, including 5,699 hypomethylated and 2,121 hypermethylated DMPs. Further analysis identified 57 genes that were enriched for DMPs in their respective promoters; many are involved in immune response, including 2 previously established SS genetic risk loci. Bioinformatics analysis highlighted an extended region of hypomethylation surrounding PSMB8 and TAP1, consistent with an increased frequency of antigen-presenting cells in LSG tissue from the SS cases. Transcription factor motif enrichment analysis revealed the specific nature of the genome-wide methylation differences, demonstrating colocalization of SS-associated DMPs with stress- and immune response-related motifs. CONCLUSION: Our findings underscore the utility of CpG methylotyping as an independent probe of active disease processes in SS, offering unique insights into the composition of disease-relevant tissue. Methylation profiling implicated several genes and pathways previously thought to be involved in disease-related processes, as well as a number of new candidates.

Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay.

IMPORTANCE: Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms. OBJECTIVE: To determine whether preeclampsia is associated with ASD and/or DD. DESIGN, SETTING, AND PARTICIPANTS: The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n = 350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status. EXPOSURES: Preeclampsia and placental insufficiency were self-reported and abstracted from medical records. MAIN OUTCOMES AND MEASURES: The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection. RESULTS: Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P = .02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64). CONCLUSIONS AND RELEVANCE: Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

Impact of exercise stress testing on diagnostic gene expression in patients with obstructive and nonobstructive coronary artery disease.

A blood-based gene expression test can diagnose obstructive coronary artery disease (CAD). The test is sensitive to inflammatory and immune processes associated with atherosclerosis. Acute exercise engages short-term inflammatory pathways, and exercise stress testing may affect results of gene expression testing during the same diagnostic workup. The objective of this study was to evaluate the effect of exercise on diagnostic gene expression testing. Ten patients with obstructive CAD (≥50% stenosis) and 10 with no/minimal CAD (≤20% stenosis) were identified by angiography. Blood samples for gene expression were obtained at baseline, peak exercise, 30 to 60 minutes after testing, and 24 to 36 hours after testing. Core-lab gene expression analysis yielded raw gene expression scores (GES) for each time point. Linear models were used to estimate changes in GES, adjusting for CAD status and other covariates. GES increased during peak exercise across both genders, with no significant differences as a function of CAD status. The overall adjusted mean GES increase at peak exercise was 0.29 (95% confidence interval 0.22 to 0.36; p <0.001). GES after exercise were not significantly different from baseline. The change in gene expression levels during peak exercise may reflect a transient inflammatory response to acute exercise that may be independent of patient gender or CAD status. In conclusion, CAD GES increase at peak exercise testing and rapidly return to baseline. Such may reflect a transient inflammatory response to acute exercise independent of gender or extent of CAD.

Infertility and its treatments in association with autism spectrum disorders: a review and results from the CHARGE study.

Previous findings on relationships between infertility, infertility therapies, and autism spectrum disorders (ASD) have been inconsistent. The goals of this study are first, to briefly review this evidence and second, to examine infertility and its treatments in association with having a child with ASD in newly analyzed data. In review, we identified 14 studies published as of May 2013 investigating infertility and/or its treatments and ASD. Overall, prior results showed little support for a strong association, though some increases in risk with specific treatments were found; many limitations were noted. In new analyses of the CHildhood Autism Risk from Genetics and the Environment (CHARGE) population-based study, cases with autism spectrum disorder (ASD, n = 513) and controls confirmed to have typical development (n = 388) were compared with regard to frequencies of infertility diagnoses and treatments overall and by type. Infertility diagnoses and treatments were also grouped to explore potential underlying pathways. Logistic regression was used to obtain crude and adjusted odds ratios overall and, in secondary analyses, stratified by maternal age (≥35 years) and diagnostic subgroups. No differences in infertility, infertility treatments, or hypothesized underlying pathways were found between cases and controls in crude or adjusted analyses. Numbers were small for rarer therapies and in subgroup analyses; thus the potential for modest associations in specific subsets cannot be ruled out. However, converging evidence from this and other studies suggests that assisted reproductive technology is not a strong independent risk factor for ASD. Recommendations for future studies of this topic are provided.

Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders.

OBJECTIVE: We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in specific domains of development in the offspring. METHODS: Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children's diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother. RESULTS: All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10-2.37; odds ratio: 2.35 [95% confidence interval: 1.43-3.88], respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite). CONCLUSIONS: Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.