Surviving cardiac arrest after carbon monoxide poisoning treated with hyperbaric oxygen therapy.

Carbon monoxide (CO) and cyanide poisoning are frequent causes of morbidity and mortality in cases of house and industrial fires. The 14th edition of guidelines from the Undersea and Hyperbaric Medical Society does not recommend hyperbaric oxygen (HBO2) treatment in those patients who have suffered a cardiac arrest and had to receive cardiopulmonary resuscitation. In this paper, we describe the case of a 31-year-old patient who received HBO2 treatment in the setting of cardiac arrest and survived.

Increased Risk of Parental Instability for Children Born Very Preterm and Impacts on Neurodevelopmental Outcomes at Age 12.

Caring for a child born preterm places significant emotional and financial burdens on family relationships. This paper examines (a) the extent to which children born very and extremely preterm are more likely to experience parental change/caregiver instability than children born full term, (b) predictors of parental change/s for preterm infants, and (c) whether exposure to parental change/caregiver instability increases child neurodevelopmental risk. Data were collected as part of a prospective longitudinal study of 110 very preterm and 113 full-term born infants and their parents studied from birth to corrected age 12 years. At ages 2, 4, 6, 9 and 12 years, detailed information was collected about the frequency and nature of all parent/caregiver changes for 3-6 monthly intervals of each child's life. At age 12, all children completed a comprehensive neurodevelopmental evaluation of their emotional and behavioural adjustment, cognition, and educational achievement. Results showed that children born very preterm were at increased risk of experiencing parental/caregiver changes, with this risk being greatest for those born extremely preterm. Neonatal medical complexity, family socioeconomic disadvantage, maternal psychological wellbeing, and child neurodevelopmental impairment were associated with a higher risk of parental change. Preterm birth and exposure to parental change/instability contributed additively to poorer child outcomes. Findings support the need for family-focused neonatal and postnatal care strategies for high-risk infants, to support parents as well as their infants to optimize child health and developmental outcomes.

The potential of school-based WASH programming to support children as agents of change in rural Zambian households.

BACKGROUND: Water, sanitation, and hygiene (WASH) interventions frequently assume that students who learn positive WASH behaviors will disseminate this information to their families. This is most prominent in school-based programs, which rely on students to act as "agents of change" to translate impact from school to home. However, there is little evidence to support or contradict this assumption. METHODS: We conducted a quasi-experimental, prospective cohort study in 12 schools in rural, southern Zambia to measure the impact of WASH UP!, a school-based WASH program designed by the creators of Sesame Street. WASH UP! is an educational program that uses stories and interactive games to teach students in grades 1-4 about healthy behaviors, such as washing hands and using the latrine. We completed in-person interviews with grade 1 and 4 students (N = 392 and 369, respectively), their teachers (N = 24) and caregivers (N = 729) using structured surveys containing both open- and closed-ended questions. We measured changes in knowledge and whether students reported sharing WASH-related messages learned in school with their caregivers at home. RESULTS: Student knowledge increased significantly, but primarily among students in grade 1. Overall rates of students reporting that they shared messages from the curriculum with their caregivers rose from 7 to 23% (p <  0.001). Students in grade 4 were 5.2 times as likely as those in grade 1 to report sharing a WASH-related message with their caregivers (ARR = 5.2, 95% C.I. = (2.3, 8.9); p <  0.001). CONCLUSIONS: Although we measured only modest levels of student dissemination of WASH UP! messages from the school to the home, students in grade 4 showed significantly more promise as agents of change than those in grade 1. Future work should prioritize developing curricula that reflect the variability in needs, capabilities and support in the home and community among primary school students rather than a single approach for a wide range of ages and contexts.

Preschool Language Development of Children Born to Women with an Opioid Use Disorder.

Increasing evidence suggests that prenatal exposure to opioids may affect brain development, but limited data exist on the effects of opioid-exposure on preschool language development. Our study aimed to characterize the nature and prevalence of language problems in children prenatally exposed to opioids, and the factors that support or hinder language acquisition. A sample of 100 children born to pregnant women in methadone maintenance treatment and 110 randomly identified non-exposed children were studied from birth to age 4.5 years. At 4.5 years, 89 opioid-exposed and 103 non-exposed children completed the preschool version of the Clinical Evaluation of Language Fundamentals (CELF-P) as part of a comprehensive neurodevelopmental assessment. Children prenatally exposed to opioids had poorer receptive and expressive language outcomes at age 4.5 years compared to non-opioid exposed children. After adjustment for child sex, maternal education, other pregnancy substance use, maternal pregnancy nutrition and prenatal depression, opioid exposure remained a significant independent predictor of children's total CELF-P language score. Examination of a range of potential intervening factors showed that a composite measure of the quality of parenting and home environment at age 18 months and early childhood education participation at 4.5 years were important positive mediators.

Prenatal methadone exposure and child developmental outcomes in 2-year-old children.

AIM: To examine the developmental outcomes of children born to opioid-dependent females enrolled in methadone maintenance and identify pre- and postnatal factors that place these children at developmental risk. METHOD: Ninety-nine methadone-maintained females and their 100 infants (42 females, 58 males, mean gestational age 38.8wks) were recruited during pregnancy/at birth and studied to age 2 years alongside a regionally representative comparison group of 108 non-methadone-maintained females and their 110 infants (62 females, 48 males, mean gestational age 39.2wks). Information about perinatal exposure was collected from medical records, maternal urine and infant meconium toxicological analysis, maternal interviews (at birth and at 18mo), and a home visit (at 18mo). At age 2 years, child neuromotor function, cognition, language, and emotional/behavioral dysregulation were assessed. RESULTS: Opioid-exposed children achieved lower motor, cognitive, and language scores and had poorer self, emotional, eating/feeding, and sensory processing regulation than unexposed children. After adjustment for maternal education and other substance use in pregnancy, between-group differences in child motor, cognitive, and overall dysregulation remained. Postnatal parental and family factors explained a further 40% to 52% of between-group differences in child outcomes. INTERPRETATION: These children and families are extremely high-risk and need antenatal and postnatal support. Children exposed to opioids during pregnancy have pervasive developmental difficulties by age 2 years. These challenges are largely explained by adverse pregnancy and socio-environmental exposures, emphasizing the importance of specialist prenatal care and postnatal intervention support. What this paper adds Children born to opioid-dependent females are at high risk of pervasive developmental problems. These problems span a range of functional domains, including motor, cognitive, language, and behavioral/emotional dysregulation. Contributing factors include other adverse pregnancy exposures, postnatal environmental factors, and the direct effects of prenatal opioid exposure.

Emotional and Behavioral Trajectories of 2 to 9 Years Old Children Born to Opioid-Dependent Mothers.

Maternal opioid use in pregnancy has increased dramatically. Knowledge about children's longer-term emotional and behavioral development after prenatal opioid exposure is scarce. A regional sample of 89 opioid-exposed and 104 non-exposed comparison children were studied prospectively at ages 2, 4.5, and 9 years using the Strengths and Difficulties Questionnaire (SDQ) completed by primary caregivers. Across all childhood assessments, opioid-exposed children obtained significantly higher total difficulties scores than non-exposed comparison children. Growth curve modeling revealed that, relative to their same age peers, opioid-exposed children's emotional and behavioral difficulties significantly worsened over time. Moreover, fixed effects estimates showed that total difficulties trajectories were poorer for children subject to higher prenatal risk (Est = 1.78, 95% CI = [0.46, 3.09]) who were born to mothers with high levels of social adversity (1.11 [0.51, 1.71]), and were then raised in families characterized by high levels of psychosocial risk (1.94 [0.90, 2.98]) and unstable caregiving (1.91 [0.33, 3.48]). A complex set of pre- and postnatal processes contribute to opioid-exposed children's emotional and behavioral development. Efforts to mitigate the long-term consequences of opioid use in pregnancy need to consider both children's and their caregivers' biopsychosocial risks.

Health and Neurodevelopment of Children Born to Opioid-Dependent Mothers at School Entry.

OBJECTIVE: To examine the school readiness of a regional cohort of prenatally methadone-exposed children across 5 domains and to examine factors contributing to impairment risk. METHODS: Data were drawn from a single-center, prospective longitudinal study. One hundred children born to women in methadone maintenance treatment and 110 randomly identified non-methadone-exposed children were studied from birth (2003-2008) to age 4.5 years. At 4.5 years, children underwent comprehensive assessment of their physical/motor development, social-emotional skills, approaches to learning, language development, and cognitive functioning. Predictors of children's overall school readiness were examined, including the extent of prenatal substance exposure (number and quantity of different substances), social risk, maternal mental health, infant clinical factors, and the quality of the home environment at age 18 months Home Observation for Measurement of the Environment (HOME) score. RESULTS: Methadone-exposed children had higher rates of delay/impairment across all outcome domains (odds ratios 4.0-5.3), with 72% impaired in at least 1 domain. Multiple problems were also common, affecting 48% of methadone-exposed children compared with 15% of control children. The mean number of school readiness domains impaired increased, with increasing prenatal substance exposure (rate ratio [RR] = 1.05 [1.01-1.11]), higher social risk (RR = 1.35 [1.20-1.53]), male sex (RR = 1.69 [1.27-2.25]), and lower HOME scores indicating a poorer quality postnatal environment (RR = 0.96 [0.94-0.99]). CONCLUSION: Children born to opioid-dependent mothers are at high risk of impaired school readiness, with multiple domain problems being common. Impaired school readiness was associated with greater maternal prenatal substance use, higher social risk, male sex, and lower-quality caregiving environments.

Neurodevelopmental Outcomes of Children Born to Opioid-Dependent Mothers: A Systematic Review and Meta-Analysis.

BACKGROUND: Children born to opioid-dependent mothers are at risk of adverse neurodevelopment. The magnitude of this risk remains inconclusive. OBJECTIVE: To conduct a meta-analysis of studies that assessed neurodevelopmental outcomes of children aged 0 to 12 years born to opioid-dependent mothers, compared with children born to nonopioid-dependent mothers, across general cognitive, language, motor, and social-emotional domains. DATA SOURCES: PubMed, CINAHL, PsycINFO, and Google Scholar databases. STUDY ELIGIBILITY CRITERIA: English-language publications between January 1993 and November 2018, including prenatally opioid-exposed and nonopioid-exposed comparison children, reporting outcomes data on standardized assessments. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently extracted data. Pooled standardized mean differences (SMDs) were analyzed using random effects models. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale. RESULTS: Across 16 studies, individual domain outcomes data were examined for between 93 to 430 opioid-exposed and 75 to 505 nonopioid-exposed infants/children. Opioid-exposed infants and children performed more poorly than their nonopioid-exposed peers across all outcomes examined, demonstrated by lower infant cognitive (SMD = 0.77) and psychomotor scores (SMD = 0.52), lower general cognition/IQ (SMD = 0.76) and language scores (SMD = 0.65-0.74), and higher parent-rated internalizing (SMD = 0.42), externalizing (SMD = 0.66), and attention problems (SMD = 0.72). LIMITATIONS: Most studies examined early neurodevelopment; only 3 reported school-age outcomes thereby limiting the ability to assess longer-term impacts of prenatal opioid exposures. CONCLUSIONS AND IMPLICATIONS OF FINDINGS: Children born to opioid-dependent mothers are at modest- to high-risk of adverse neurodevelopment at least to middle childhood. Future studies should identify specific clinical and social factors underlying these challenges to improve outcomes.

Educational achievement at age 9.5 years of children born to mothers maintained on methadone during pregnancy.

Recent research shows that preschool children born to opioid-dependent mothers are at increased risk for cognitive, psychomotor, attention, and social-emotional adjustment problems. But very little is known about their school-age functioning, particularly their educational achievement. This analysis examined the educational outcomes of a regional cohort of 100 prenatally methadone-exposed children who were prospectively studied from birth to age 9.5 years alongside a comparison group of 110 randomly identified non-exposed children born between 2003 and 2008. At age 9.5, as part of a comprehensive neurodevelopmental evaluation, children's teachers rated their achievement across the school curriculum, and children completed the Woodcock Johnson-III Tests of Achievement (WJ-III). Detailed information about the birth mother's social background, pregnancy substance use, and mental health was also collected during pregnancy/at term. Infant clinical data were collected after birth. Methadone-exposed children performed less well than non-exposed children across seven school curriculum areas rated by teachers (ps ≤.001), performed less well than non-exposed children on all reading and mathematics subtests of the WJ-III, and had higher rates of any educational delay on the WJ-III (57% vs. 15%), OR = 7.47 (3.71-15.02). Results were similar when children with severe intellectual impairment were excluded. After adjusting for confounding factors, methadone-exposed children had increased odds of educational delay, but this was only marginally significant (OR = 3.62, [1.01-13.01], p = .049). Maternal educational attainment level (OR = 0.69, [0.50-0.89], p = .006), and maternal benzodiazepine use during pregnancy (OR = 2.70 [1.03-7.12], p = .044) were also associated with later educational risk. Findings suggest that children born to opioid-dependent women enrolled in methadone maintenance are at high risk of educational delay by age 9.5 years. Children's academic difficulties appeared to reflect the effects of both adverse prenatal exposures and postnatal social risk.

STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial.

BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL. METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 dose-escalation study.