Neuropsychological assessment of adults with phenylketonuria using the NIH toolbox.

Among researchers and clinicians, there is a call for the development and validation of new measures to better assess and characterize neurocognitive difficulties associated with early-treated phenylketonuria (ETPKU) and other metabolic disorders. The NIH Toolbox represents a relatively new computer-administered assessment tool and provides a sampling of performance across multiple cognitive domains, several of which (e.g., executive function, processing speed) are at risk for disruption in ETPKU. The goal of the present study was to provide an initial evaluation of the value and sensitivity of the NIH Toolbox for use with individuals with ETPKU. To this end, a sample of adults with ETPKU and a demographically-matched comparison group without PKU completed the cognitive and motor batteries of the Toolbox. Results indicate that overall performance (as reflected by the Fluid Cognition Composite) was sensitive to both group differences (ETPKU vs non-PKU) as well as blood Phe levels (a marker of metabolic control). The present findings offer preliminary support for the utility of the NIH Toolbox as a measure of neurocognitive functioning in individuals with ETPKU. Future research including a larger sample size and broader age range is needed to fully validate the Toolbox for clinical and research use with individuals with ETPKU.

Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study.

Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E. coli Nissle 1917, designated SYNB1618, through insertion of the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase into the genome, which allow for bacterial consumption of Phe within the gastrointestinal tract. SYNB1618 was studied in a phase 1/2a randomized, placebo-controlled, double-blind, multi-centre, in-patient study ( NCT03516487 ) in adult healthy volunteers (n = 56) and patients with PKU and blood Phe level ≥600 mmol l-1 (n = 14). Participants were randomized to receive a single dose of SYNB1618 or placebo (part 1) or up to three times per day for up to 7 days (part 2). The primary outcome of this study was safety and tolerability, and the secondary outcome was microbial kinetics. A D5-Phe tracer (15 mg kg-1) was used to study exploratory pharmacodynamic effects. SYNB1618 was safe and well tolerated with a maximum tolerated dose of 2 × 1011 colony-forming units. Adverse events were mostly gastrointestinal and of mild to moderate severity. All participants cleared the bacteria within 4 days of the last dose. Dose-responsive increases in strain-specific Phe metabolites in plasma (trans-cinnamic acid) and urine (hippuric acid) were observed, providing a proof of mechanism for the potential to use engineered bacteria in the treatment of rare metabolic disorders.

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

Maternal Depressive Symptoms and At-Risk Young Children's Internalizing Problems: The Moderating Role of Mothers' Positivity.

Maternal depressive symptoms predict negative child behaviors, including internalizing problems. However, protective factors, such as positive emotionality and positive parenting behaviors, may play an important a role in attenuating associations between maternal depressive symptoms and child behavior problems. This manuscript presents two studies that examined buffers of links between maternal depressive symptoms and child internalizing problems. Each study examined samples of primarily African American families with young children in an impoverished large city in the Midwestern United States. Families were recruited from kindergarten classes and Women, Infants, and Children (WIC) centers. In both studies, indicators of mothers' positivity, as measured by text based analysis of positive emotion word use or behavioral observation of positive parenting behaviors, attenuated links between maternal depressive symptoms and child internalizing problems. The results suggest that risk for internalizing problems within the context of maternal depressive symptoms is reduced when parents experience and express more positive emotions and behaviors.

Temperament, personality, and quality of life in pediatric cancer patients.

OBJECTIVE: The developmental psychology literature shows that children with higher levels of effortful control (EC) and ego-resilience (ER) display greater social competence and better emotional adjustment. This study examined whether these dispositional attributes contribute to positive quality of life (QOL) in pediatric cancer patients. METHOD: Participants were 103 pediatric cancer patients (and their parents) who were part of a larger parent study. At study entry, parents reported their own anxiety and depression and their children's EC and ER. At 3-month follow-up, parents reported children's QOL. RESULTS: ER was positively correlated with children's QOL. EC showed a positive indirect effect on QOL through ER. Inclusion of potential correlates of pediatric QOL (e.g., parent neuroticism) did not change these relationships. CONCLUSIONS: Temperament and personality play significant roles in pediatric cancer patients' QOL. Assessing dispositional attributes early in treatment may help identify children at risk for poor QOL during and after treatment.

Longitudinal prediction of disruptive behavior disorders in adolescent males from multiple risk domains.

The disruptive behavior disorders are among the most prevalent youth psychiatric disorders, and they predict numerous problematic outcomes in adulthood. This study examined multiple domains of risk during early childhood and early adolescence as longitudinal predictors of disruptive behavior disorder diagnoses among adolescent males. Early adolescent risks in the domains of sociodemographic factors, the caregiving context, and youth attributes were examined as mediators of associations between early childhood risks and disruptive behavior disorder diagnoses. Participants were 309 males from a longitudinal study of low-income mothers and their sons. Caregiving and youth risk during early adolescence each predicted the likelihood of receiving a disruptive behavior disorder diagnosis. Furthermore, sociodemographic and caregiving risk during early childhood were indirectly associated with disruptive behavior disorder diagnoses via their association with early adolescent risk. The findings suggest that preventive interventions targeting risk across domains may reduce the prevalence of disruptive behavior disorders.

An overview of the "Positive Action for Today's Health" (PATH) trial for increasing walking in low income, ethnic minority communities.

BACKGROUND: Ethnic minorities and lower-income adults have among the highest rates of obesity and lowest levels of regular physical activity (PA). The Positive Action for Today's Health (PATH) trial compares three communities that are randomly assigned to different levels of an environmental intervention to improve safety and access for walking in low income communities. DESIGN AND SETTING: Three communities matched on census tract information (crime, PA, ethnic minorities, and income) were randomized to receive either: an intervention that combines a police-patrolled-walking program with social marketing strategies to promote PA, a police-patrolled-walking only intervention, or no-walking intervention (general health education only). Measures include PA (7-day accelerometer estimates), body composition, blood pressure, psychosocial measures, and perceptions of safety and access for PA at baseline, 6, 12, 18, and 24 months. INTERVENTION: The police-patrolled walking plus social marketing intervention targets increasing safety (training community leaders as walking captains, hiring off-duty police officers to patrol the walking trail, and containing stray dogs), increasing access for PA (marking a walking route), and utilizes a social marketing campaign that targets psychosocial and environmental mediators for increasing PA. MAIN HYPOTHESES/OUTCOMES: It is hypothesized that the police-patrolled walking plus social marketing intervention will result in greater increases in moderate-to-vigorous PA as compared to the police-patrolled-walking only or the general health intervention after 12 months and that this effect will be maintained at 18 and 24 months. CONCLUSIONS: Implications of this community-based trial are discussed.