Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Improving Neonatal Follow-up: A Quality Improvement Study Analyzing In-hospital Interventions and Long-term Show Rates.

Neonatal follow-up (NFU) clinics play an essential role in the multidisciplinary care of preterm patients. Despite the inherent value of NFU clinics, many clinical programs report poor compliance with follow-up visits. Preterm infants followed with difficulty in the long-term have higher rates of disability and lower IQ scores, even after adjustment of significant perinatal and sociodemographic variables. This quality improvement study aimed to improve the show rate for preterm infants from 60% to 80% at the initial 6-month adjusted age visit by implementing a multilevel education bundle. METHODS: Participants included neonatal intensive care unit (NICU) physicians, physician extenders, registered nurses, and parents of preterm patients admitted to the NICU who qualified for NFU. Our 75-bed NICU is the regional perinatal center within an urban free-standing children's hospital. Our bundle included NICU provider education, discharge planning, and parent education. A tracking system was developed to identify qualifying patients to streamline workflow. RESULTS: The monthly first visit show rate improved from 60% to 76% during the intervention period. Seventy-five percent of families who received parent education presented for their initial visit, compared to 51% of families who did not receive parent education. In anonymous surveys of families who presented for their initial visits, 95% indicated that bedside education played the most important role in appointment attendance. Interdisciplinary rounds are crucial for reaching all families before discharge. CONCLUSION: Implementing a multidimensional in-hospital education bundle and tracking system is feasible and can improve NFU clinic show rates, but may require dedicated personnel for sustainability.

Constructing a Culturally Informed Spanish Decision-Aid to Counsel Latino Parents Facing Imminent Extreme Premature Delivery.

Objective How Latino parents perceive and understand antenatal counseling for extreme prematurity, < 26 weeks of gestational age (GA), is not clear. We aim to characterize Latino parental perceptions of antenatal counseling in order to construct and validate a Spanish decision-aid (SDA) to improve parental knowledge of prematurity after antenatal consults. Methods This is a three-phased, prospective, multicenter study. First, interviews of 22 Latino parents with a history of birth < 26 weeks GA were conducted. Thematic analysis identified themes valued during antenatal counseling for decisions regarding neonatal resuscitation. Next, we incorporated these themes into the SDA. Finally, improvement in knowledge of prematurity in two Spanish-speaking groups, 'experienced' parents with a history of extremely premature birth and 'naïve' adult Latino volunteers, was measured using a multiple choice test before and after simulated counseling with the SDA. Result Twenty-two interviews generated seven unique themes. An SDA was constructed that preserved six themes paralleled by those found in a previously studied English population, and addressed a novel theme of "intercultural linguistic barriers" unique to our population. Knowledge scores rose in "naive" volunteers, 41 ± 12% to 71 ± 15% (P < 0.001), after simulated counseling with the SDA. 'Experienced' parents had a ceiling effect in knowledge scores, 62 ± 9% to 65 ± 11% (P = 0.22). The SDA was well received by participants. Conclusions for Practice Interviews of Latino parents with a history of premature birth generated similar themes to English-speaking parents, with intercultural linguistic barriers as a novel theme. An SDA for Latino parents facing extremely premature birth may improve comprehension of antenatal counseling.

Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study.

PURPOSE: To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age. METHODS: This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age. RESULTS: BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors. CONCLUSION: CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.

Caregiver traumatization adversely impacts young children's mental representations on the MacArthur Story Stem Battery.

The aim of our study was to investigate the impact of maternal exposure to family violence, maltreatment, and related posttraumatic stress disorder (PTSD) on young children's mental representations of self and caregivers. Participant mothers (n=24) and children (n=25) were recruited from a referred sample when they were 4-7 years old. Maternal report and child story stem narratives were used. Mother's experience of domestic violence and severity of violence-related PTSD symptoms robustly predicted more dysregulated aggression, attentional bias to danger and distress, as well as more avoidance of and withdrawal from conflicts presented in the children's story stems. Less narrative coherence was also noted. Traumatized mothers experience and symptoms prior to their child's turning 4 years old adversely affected their child's mental representations from 4-7 years.

Child mental representations of attachment when mothers are traumatized: The relationship of family-drawings to story-stem completion.

This study examines the relationship between child play-narratives and family drawings by children of violence-exposed mothers with posttraumatic stress disorder (PTSD). The Family Attachment Drawing Task (FAD-T) and MacArthur Story Stem Battery (MSSB) were administered. Of the 23 children (ages 4-7 years), 16 (70%) created drawings that were coded as being representative of insecure attachment. Attachment insecurity and disorganization of child-caregiver attachment on the FAD-T were significantly associated with trauma-related dimensions of the MSSB, but not to other factors. This study suggests that the FAD-T provides access to child mental representations, which may affect intergenerational transmission of violent trauma.

Interventions to improve medication adherence in schizophrenia.

OBJECTIVE: Although nonadherence with the antipsychotic medication regimen is a common barrier to the effective treatment for schizophrenia, knowledge is limited about how to improve medication adherence. This systematic literature review examined psychosocial interventions for improving medication adherence, focusing on promising initiatives, reasonable standards for conducting research in this area, and implications for clinical practice. METHOD: Studies were identified by computerized searches of MEDLINE and PsychLIT for the years between 1980 and 2000 and by manual searches of relevant bibliographies and conference proceedings. Key articles were summarized. RESULTS: Thirteen (33%) of 39 identified studies reported significant intervention effects. Although interventions and family therapy programs relying on psychoeducation were common in clinical practice, they were typically ineffective. Concrete problem solving or motivational techniques were common features of successful programs. Interventions targeted specifically to problems of nonadherence were more likely to be effective (55%) than were more broadly based treatment interventions (26%). One-half (four of eight) of the successful interventions not specifically focused on nonadherence involved an array of supportive and rehabilitative community-based services. CONCLUSIONS: Psychoeducational interventions without accompanying behavioral components and supportive services are not likely to be effective in improving medication adherence in schizophrenia. Models of community care such as assertive community treatment and interventions based on principles of motivational interviewing are promising. Providing patients with concrete instructions and problem-solving strategies, such as reminders, self-monitoring tools, cues, and reinforcements, is useful. Problems in adherence are recurring, and booster sessions are needed to reinforce and consolidate gains.