Multiple Tools Are Needed for the Detection of Prenatal Alcohol Exposure: Findings From a Community Antenatal Setting.

BACKGROUND: Although the toxic effects of prenatal alcohol exposure (PAE) on children are well established, there is emerging evidence about the dynamics and associated demographics of drinking patterns across pregnancy, with risky drinking more likely to take place in the period before pregnancy awareness. This study investigated the use of complementary measurement tools in the understanding of alcohol use across pregnancy and reports on the rates and patterns of alcohol use in a community antenatal setting. METHODS: Data on alcohol consumption before and after awareness of pregnancy were collected via multiple measurement tools: anonymous lifestyle questionnaire, TWEAK (Tolerance, Worried, Eye-opener, Amnesia, K/Cut down) screener questionnaire, and Substance Use Inventory interviews across multiple pregnancy timepoints. Additionally, phosphatidylethanol (PEth), a direct biomarker of alcohol metabolism, collected from newborns' dried blood spot cards, was analyzed. RESULTS: The TWEAK screener was more likely to identify risky drinking behavior than the lifestyle questionnaire. When pregnancy was unplanned, women were more likely to find out they are pregnant significantly later (p < 0.001) and consume alcohol at moderate-heavy levels (p = 0.03), prolonging the risk to the fetus. There was an association between maternal self-reported alcohol use on the lifestyle questionnaire and Substance Use Inventory interviews, but no association between maternal reports of alcohol use and PEth results (p = 0.72). Women self-reported moderate-heavy alcohol use in early pregnancy only and a positive PEth screen indicated PAE in late pregnancy, suggesting that these methods may identify different groups of women. CONCLUSIONS: Multiple measurement tools and methods are needed to identify PAE at different points across pregnancy. Prospective sensitive interviewing is better suited to detecting PAE in early pregnancy, but not later when social desirability bias is stronger, and the use of an objective biomarker, such a PEth, may be useful for identifying the risk of PAE in late pregnancy.

Post-discharge outcomes for mothers and the mother-infant relationship following admission to a psychiatric Mother-Baby Unit.

Mother-Baby Unit research has focussed on maternal psychopathology over the course of an admission. Less is known about the baby's well-being, the shared relationship, or the mother's recovery. In an initial sample of 45 women, we describe discharge and post-discharge outcomes for maternal psychopathology (using maternal report and the Global Assessment of Function, GAF) and the mother-infant relationship (using the Child and Adult Relational Experimental Index, CARE Index). Three months post-discharge, one third of women described themselves as "completely recovered," one third were experiencing significant deterioration and 17% were readmitted to inpatient care. Poorer GAF scores were associated with a clinical diagnosis of comorbid personality disorder, antenatal presence of the index illness, partner illicit substance use, maternal perception of her bond, infant social withdrawal, and child protection concern. Post-discharge, the mother-infant relationship results were concerning. Only 17% were regarded as adequate. Improvement was observed across this period in 56% but relational deterioration occurred for 35%. Maternal and relational outcomes were weakly correlated at discharge (r² = 0.29, p = 0.07) but this was lost post-discharge (r² = 0.03, p = 0.89). The shared relationship and infant mental health should both be targets for intervention; both during MBU admission, and post-discharge.

La investigación sobre la Unidad de Madres y Bebés se han enfocado en la sicopatología materna a lo largo del curso de una admisión. Se conoce menos del bienestar del bebé, la relación entre ellos o la presente recuperación de la madre. En un grupo muestra inicial de 45 mueres, describimos resultados posteriores a cuando se les dio de alta en cuanto a la sicopatología materna (usando el reporte materno y la Evaluación Global de la Función, GAF) y la relación infante-madre (usando el Índice de Relación Experimental entre Niño y Adulto, Índice CARE). Tres meses después de que se les dio de alta, un tercio de las mujeres se describió a sí mismas como "completamente recuperadas," un tercio de ellas estaba experimentando un deterioro significativo y 17% fueron readmitidas bajo el cuidado de paciente interno. Los más pobres puntajes de GAF se asociaron con un diagnóstico clínico de trastornos de personalidad comórbidos, presencia antenatal de la enfermedad en el índice, uso ilícito de sustancias por parte de la pareja, percepción maternal de su unión afectiva, despego social del infante, así como la preocupación por la protección del infante. Después de que se les diera de alta, los resultados de la relación entre madre e infante fueron preocupantes. Sólo el 17% fue considerado adecuado. Se observaron mejoras a lo largo de este período en 56% pero el deterioro de la relación ocurrió en el 35%. El resultado materno y el de relación fueron asociados débilmente al momento de darles de alta (r2+0.29. p = 0.07) pero esto se perdió posteriormente al momento en que se les dio de alta. La relación compartida y la salud mental del infante deben ambas ser metas de intervención; ambas durante la admisión a la Unidad de Madres y Bebés y con posterioridad al momento en que se les da de alta.

Les recherches sur l'Unité psychiatrique Maman Bébé (en anglais Mother Baby Unit) ont porté sur la psychopathologie maternelle au cours d'une admission. On sait moins de choses sur le bien-être du bébé, leur relation ou la récupération en cours de la mère. Dans un échantillon initial de 45 femmes, nous décrivons des résultats à la sortie pour la psychopathologie maternelle (en utilisant le rapport maternel et l'Evaluation Globale de Fonction, soit GAF pour Global Assessment of Function en anglais) et la relation mère-bébé (en utilisant l'Index Expérimental Relationnel Enfant et Adulte, soir CARE Index, pour Child and Adult Relational Experimental Index en anglais). Trois mois après la sortie, un tiers des mères se décrivaient comme "ayant totalement récupéré", un tiers faisaient l'expérience d'une détérioration importante et 17% étaient réadmises en soins hospitaliers. Des scores GAF moins élevés étaient liés à un diagnostic clinique de trouble de la personnalité comorbide, à une présence anténatale de la maladie index, à une toxicomanie illicite du partenaire, à une perception maternelle de son lien, au retrait social du bébé et à des inquiétudes pour la protection de l'enfant. Après la sortie les résultats de la relation mère-bébé étaient inquiétants. Seuls 17% des résultats ont été considérés comme étant adéquats. Une amélioration a été observée durant cette période chez 56% mais une détérioration relationnelle a eu lieu pour 35%. Les résultats maternels et relationnels étaient faiblement corrélés à la sortie (r² = 0s29, p = 0,07) mais cela s'est avéré perdu après la sortie (r² = 0,03, p = 0,89). La relation partagée et la santé mentale du bébé devraient être tous deux des cibles d'intervention; à la fois durant l'admission dans l'Unité Maman Bébé et aussi après la sortie. Mots clés: bébé, après la sortie, unité maman bébé, santé mentale périnatale, relation mère-bébé.

MOTHERS AND THEIR INFANTS CO-ADMITTED TO A NEWLY DEVELOPED MOTHER-BABY UNIT: CHARACTERISTICS AND OUTCOMES.

Research on Mother-Baby Units (MBUs) has mainly focused on maternal psychiatric outcomes, not the well-being of infants. This study investigated infant development and mental health along with maternal characteristics and the mother-infant relationship in 45 dyads (60% New Zealand European, 20% Maori, 11% Pacific) admitted to a new MBU. Maternal psychopathology was measured with the Health of the Nations Outcome Scale (HoNOS, J.K Wing et al., 1998) and Global Assessment of Functioning (GAF; I.M. Aas, 2010). The Parent-Infant Relationship Global Assessment Scale (PIR-GAS, Zero to Three, 2005) measured the mother-infant relationship. Infant measures included Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (Zero to Three Press, 2005) and the Ages & Stages-3 (J. Squires, E. Twombly, D. Bricker, & L. Potter, 2009). Maternal mental illness and functioning improved during the admission and were positively associated with longer inpatient duration and no illicit substance use. Well-being of the infants was concerning. In addition to lower birth weights and poorer health status, at discharge 51% were lagging behind developmentally, and 51% were exhibiting signs of infant mental health concerns. Relationally, 67% of mother-infant dyads had features of, and 29% met criteria for, a disordered relationship. Poorer mother-infant relationships were associated with a maternal diagnosis of schizophrenia or bipolar disorder, use of the Mental Health Act, leaving the MBU early, limited social support, and infant mental health diagnosis.

Executive Function Is Associated With Off-Line Motor Learning in People With Chronic Stroke.

BACKGROUND AND PURPOSE: Sleep has been shown to promote off-line motor learning in individuals following stroke. Executive function ability has been shown to be a predictor of participation in rehabilitation and motor recovery following stroke. The purpose of this study was to explore the association between executive function and off-line motor learning in individuals with chronic stroke compared with healthy control participants. METHODS: Seventeen individuals with chronic stroke (>6 months poststroke) and 9 healthy adults were included in the study. Participants underwent 3 consecutive nights of polysomnography, practiced a continuous tracking task the morning of the third day, and underwent a retention test the morning after the third night. Participants underwent testing on 4 executive function tests after the continuous tracking task retention test. RESULTS: Participants with stroke showed a significant positive correlation between the off-line motor learning score and performance on the Trail-Making Test from Delis-Kaplan Executive Function System (r = 0.652; P = 0.005), while the healthy control participants did not. Regression analysis showed that the Trail-Making Test-Delis-Kaplan Executive Function System is a significant predictor of off-line motor learning (P = 0.008). DISCUSSION AND CONCLUSIONS: This is the first study to demonstrate that better performance on an executive function test of attention and set-shifting predicts a higher magnitude of off-line motor learning in individuals with chronic stroke. This emphasizes the need to consider attention and set-shifting abilities of individuals following stroke as these abilities are associated with motor learning. This in turn could affect learning of activities of daily living and impact functional recovery following stroke.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A166).

Interactive effects of early and recent exposure to stressful contexts on cortisol reactivity in middle childhood.

BACKGROUND: Given mixed findings as to whether stressful experiences and relationships are associated with increases or decreases in children's cortisol reactivity, we tested whether a child's developmental history of risk exposure explained variation in cortisol reactivity to an experimentally induced task. We also tested whether the relationship between cortisol reactivity and children's internalizing and externalizing problems varied as a function of their developmental history of stressful experiences and relationships. METHOD: Participants included 400 children (M = 9.99 years, SD = 0.74 years) from the Children's Experiences and Development Study. Early risk exposure was measured by children's experiences of harsh, nonresponsive parenting at 3 years. Recent risk exposure was measured by children's exposure to traumatic events in the past year. Children's cortisol reactivity was measured in response to a social provocation task and parents and teachers described children's internalizing and externalizing problems. RESULTS: The effect of recent exposure to traumatic events was partially dependent upon a child's early experiences of harsh, nonresponsive parenting: the more traumatic events children had recently experienced, the greater their cortisol reactivity if they had experienced lower (but not higher) levels of harsh, nonresponsive parenting at age 3. The lowest levels of cortisol reactivity were observed among children who had experienced the most traumatic events in the past year and higher (vs. lower) levels of harsh, nonresponsive parenting in early childhood. Among youth who experienced harsh, nonresponsive parent-child relationships in early childhood and later traumatic events, lower levels of cortisol reactivity were associated with higher levels of internalizing and externalizing problems. CONCLUSIONS: Hypothalamic-pituitary-adrenal (HPA) axis reactivity to psychological stressors and the relationship between HPA axis reactivity and children's internalizing and externalizing problems vary as a function of a child's developmental history of exposure to stressful relationships and experiences.

Take your mind off it: Coping style, serotonin transporter linked polymorphic region genotype (5-HTTLPR), and children's internalizing and externalizing problems.

Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene × Environment effects on externalizing symptoms.

L-Deprenyl reverses age-associated decline in splenic norepinephrine, interleukin-2 and interferon-γ production in old female F344 rats.

UNLABELLED: Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced natural killer cell activity, interleukin (IL)-2 and interferon (IFN)-γ production, and T- and B-cell proliferation, suggesting possible links between sympathetic activity and immunosenescence. OBJECTIVES: The aim of this study is to investigate the effects of L-(-)-deprenyl, a monoamine oxidase-B inhibitor, on the sympathetic nervous system and cell-mediated immune responses in old female rats. METHODS: Low doses of L-deprenyl (0.25 or 1.0 mg/kg body weight, BW) were administered intraperitoneally to 19- to 21-month-old female F344 rats for 8 weeks. To assess the stereoselectivity of the effects of deprenyl on splenic sympathetic activity and immune responses, the D-enantiomer (D-(+)-deprenyl; 1.0 mg/kg BW) was also included in the studies. Norepinephrine (NE) concentration and content, and mitogen-induced T-cell proliferation and cytokine production were assessed in the splenocytes after deprenyl treatment. RESULTS: Treatment with L-deprenyl reversed the age-related decrease in NE concentration and content and IFN-γ production, and increased IL-2 production in the spleen while D-deprenyl did not affect the age-associated reduction in splenic NE levels or cytokine production. CONCLUSIONS: These findings demonstrate that L-deprenyl exerts neurorestorative and immunostimulatory effects on the sympathetic nervous system and cell-mediated immune responses during aging and provides evidence for a causal relationship between some aspects of immunosenescence and the age-related decline in sympathetic nerves in the spleens of female F344 rats.

Evidence for the Effectiveness and Acceptability of e-SBI or e-SBIRT in the Management of Alcohol and Illicit Substance Use in Pregnant and Post-partum Women.

Alcohol and illicit psychoactive drug use during pregnancy have increased worldwide, putting women and their children's health and development at risk. Multiple drug use, comorbid psychiatric disorders, sexual and physical abuse are common in women who use alcohol and drugs during pregnancy. The effects on the mother include poor reproductive and life-long health, legal, family, and social problems. Additionally, the exposed child is at increased risk of long-term physical health, mental health, and developmental problems. The stigma associated with substance use during pregnancy and some clinicians' reticence to inquire about substance use means many women are not receiving adequate prenatal, substance abuse, and mental health care. Evidence for mHealth apps to provide health care for pregnant and post-partum women reveal the usability and effectiveness of these apps to reduce gestational weight gain, improve nutrition, promote smoking cessation and manage gestational diabetes mellitus, and treat depression and anxiety. Emerging evidence suggests mHealth technology using a public health approach of electronic screening, brief intervention, or referral to treatment (e-SBIRT) for substance use or abuse can overcome the typical barriers preventing women from receiving treatment for alcohol and drug use during pregnancy. This brief intervention delivered through a mobile device may be equally effective as SBIRT delivered by a health care professional in preventing maternal drug use, minimizing the effects to the exposed child, and providing a pathway to therapeutic options for a substance use disorder. However, larger studies in more diverse settings with women who have co-morbid mental illness and a constellation of social risk factors that are frequently associated with substance use disorders are needed.

Genomewide association analysis of coronary artery disease.

BACKGROUND: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS: We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

5HTT genotype moderates the influence of early institutional deprivation on emotional problems in adolescence: evidence from the English and Romanian Adoptee (ERA) study.

BACKGROUND: A common polymorphism in the serotonin transporter gene (SLC6A4, 5HTT) has been repeatedly shown to moderate the influence of childhood adversity and stressful life events on the development of psychopathology. Using data from the English and Romanian Adoptee Study, a prospective-longitudinal study of individuals (n = 125) exposed to severe early institutional deprivation (ID), we tested whether the effect of ID on adolescent emotional problems is moderated by 5HTT genotype and stressful life events in adolescence. METHODS: Emotional problems were assessed using questionnaire data (age 11), and on the basis of the CAPA diagnostic interview (age 15). Additionally, the number of stressful life events was measured. RESULTS: There was a significant effect for genotype (p = .003) and a gene x environment interaction (p = .008) that was independent of age at testing. Carriers of the s/l and s/s genotype who experienced severe ID showed the highest emotional problem scores, while l/l homozygotes in the severe ID group showed the lowest overall levels. Furthermore, s/s carriers in the severe ID group who experienced a high number of stressful life events between 11 and 15 years had the largest increases in emotional problem scores, while a low number of stressful life events was associated with the largest decrease (4-way interaction: p = .05). CONCLUSIONS: The effects of severe early ID on emotional problems in adolescence are moderated by 5HTT genotype, and influenced by stressful life events in adolescence.

IX. Risk, causation, mediation, and moderation.

Throughout this monograph, there has been frequent reference to levels of risk, inference of causation, testing for mediating variables, and the need to consider possible moderating influences. In this chapter, we review what is meant by these concepts, and then seek to pull together the findings from the English and Romanian Adoptee (ERA) studies that were relevant for these issues. When the findings have been presented in detail in earlier chapters, we simply summarize the main salient points. However, with respect to possible genetic moderation of the effects of institutional deprivation, we present new data because these were not considered in earlier chapters. There was a time when most developmental research, particularly that dealing with social development, moved blithely ahead using cross-sectional studies to investigate developmental processes without consideration of the multiple complex ways in which these processes may work together or separately. That is no longer acceptable (Kraemer et al., 1997; Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001; Murray, Farrington, & Eisner, 2009; Rutter, 1988, 2009). Not only must the various processes, and their interplay, be clearly conceptualized, but also it will be essential to pit different refutable causal hypotheses against each other (Lahey, D'Onofrio, & Waldman, 2009; Rutter, 2003, 2006b).

Cognitive behavioral therapy for insomnia to enhance cognitive function and reduce the rate of Aß deposition in older adults with symptoms of insomnia: A single-site randomized pilot clinical trial protocol.

Lifestyle interventions to increase exercise and improve diet have been the focus of recent clinical trials to potentially prevent Alzheimer's disease (AD). However, despite the strong links between sleep disruptions, cognitive decline, and AD, sleep enhancement has yet to be targeted as a lifestyle intervention to prevent AD. A recent meta-analysis suggests that approximately 15% of AD may be prevented by an efficacious intervention aimed to reduce sleep disturbances and sleep disorders. Chronic insomnia is the most frequent sleep disorder occurring in at least 40% of older adults. Individuals with insomnia are more likely to be diagnosed with Alzheimer's Disease (AD) and demonstrate decline in cognitive function at long-term follow-up. AD is characterized by the accumulation of amyloid-ß (Aß) plaques and tau tangles in the brain, and growing evidence shows impaired sleep contributes to the accumulation of Aß. An intervention aimed at improving insomnia may be a critical opportunity for primary prevention to slow cognitive decline and potentially delay the onset of AD. Cognitive behavioral therapy for insomnia (CBT-I) is an efficacious treatment for insomnia, but the use of CBT-I to improve cognitive function and potentially reduce the rate of Aß accumulation has never been examined. Therefore, the objective of the proposed study is to examine the efficacy of CBT-I on improving cognitive function in older adults with symptoms of insomnia. An exploratory aim is to assess the effect of CBT-I on rate of Aß accumulation.

Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy.

OBJECTIVE/HYPOTHESIS: The ADHERE Registry is a multicenter prospective observational study following outcomes of upper airway stimulation (UAS) therapy in patients who have failed continuous positive airway pressure therapy for obstructive sleep apnea (OSA). The aim of this registry and purpose of this article were to examine the outcomes of patients receiving UAS for treatment of OSA. STUDY DESIGN: Cohort Study. METHODS: Demographic and sleep study data collection occurred at baseline, implantation visit, post-titration (6 months), and final visit (12 months). Patient and physician reported outcomes were also collected. Post hoc univariate and multivariate analysis was used to identify predictors of therapy response, defined as ≥50% decrease in Apnea-Hypopnea Index (AHI) and AHI ≤20 at the 12-month visit. RESULTS: The registry has enrolled 1,017 patients from October 2016 through February 2019. Thus far, 640 patients have completed their 6-month follow-up and 382 have completed the 12-month follow-up. After 12 months, median AHI was reduced from 32.8 (interquartile range [IQR], 23.6-45.0) to 9.5 (IQR, 4.0-18.5); mean, 35.8 ± 15.4 to 14.2 ± 15.0, P < .0001. Epworth Sleepiness Scale was similarly improved from 11.0 (IQR, 7-16) to 7.0 (IQR, 4-11); mean, 11.4 ± 5.6 to 7.2 ± 4.8, P < .0001. Therapy usage was 5.6 ± 2.1 hours per night after 12 months. In a multivariate model, only female sex and lower baseline body mass index remained as significant predictors of therapy response. CONCLUSIONS: Across a multi-institutional study, UAS therapy continues to show significant improvement in subjective and objective OSA outcomes. This analysis shows that the therapy effect is durable and adherence is high. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:1333-1338, 2020.

Upper Airway Stimulation versus Untreated Comparators in Positive Airway Pressure Treatment-Refractory Obstructive Sleep Apnea.

Rationale: Understand the impact of insurance coverage on sleep apnea outcomes for patients awaiting upper airway stimulation.Objectives: Examine the natural history of impact of upper airway stimulation treatment versus insurance denial (comparators) on sleep apnea outcomes.Methods: A parallel-arm experimental study design was used to compare objective sleep apnea measures and patient-reported outcomes in those who received upper airway stimulation approval versus denial in a multinational prospective study (NCT02907398). Wilcoxon rank-sum test and logistic regression models were used to assess for differences of objective and subjective outcome changes in those who underwent upper airway stimulation versus no treatment comparators.Results: A greater reduction in apnea-hypopnea index was observed in those who underwent upper airway stimulation (n = 230, follow-up: 360 ± 171 d) versus no treatment (n = 100, follow-up: 272 ± 278 d), that is, -19.1 ± 15.8 versus -8.1 ± 20.9, respectively, P < 0.001, with consistent findings observed with nocturnal hypoxia measures. Concordantly, a greater improvement noted with subjective measures of dozing propensity was observed in patients undergoing upper airway stimulation versus comparators (Epworth Score, -5.1 ± 5.5 vs. 1.8 ± 3.7, respectively, P < 0.001) and overall sleep-related patient-reported outcomes. Women and those with previous oral appliance use had a lower odds of insurance approval (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.22-0.71 and OR, 0.35; 95% CI, 0.18-0.69, respectively).Conclusions: Objective and subjective sleep apnea burden was more improved in those receiving upper airway stimulation versus not. Results underscore the need to optimize clinical care pathways focused on effective treatment of patients with obstructive sleep apnea who are not upper airway stimulation-insurance eligible and prioritize public health policy initiatives to address insurance-based sex-specific disparities.

Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease.

AIMS: Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease. METHODS AND RESULTS: Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease (r = 0.62, P < 0.001). CONCLUSION: The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.

Dopamine transporter gene polymorphism moderates the effects of severe deprivation on ADHD symptoms: developmental continuities in gene-environment interplay.

Early institutional deprivation is a risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. However not all individuals are affected. We tested the hypothesis that this heterogeneity is influenced by gene x environment (GxE) interaction and that genetic polymorphisms involved in dopamine neurotransmission moderate the effects of severe early institutional deprivation on symptoms of ADHD (sADHD). Using a prospective-longitudinal design sADHD were measured at ages 6, 11, and 15 years in a sample of individuals who experienced severe institutional deprivation (up to 42 months of age) in Romanian orphanages and a non-institutionalized comparison group. Individuals were genotyped for polymorphisms in the dopamine D4 receptor (DRD4 48-bp VNTR in exon 3) and dopamine transporter gene (DAT1 haplotypes combining a 40-bp VNTR in 3'UTR and a 30-bp VNTR in intron 8). The risk for sADHD associated with early institutional deprivation was moderated by the DAT1 but not the DRD4 genotypes; an effect that was first apparent in early-, and persisted to mid-adolescence. The results (i) provide evidence for developmental continuities in G x E interaction, (ii) explain some of the heterogeneity in ADHD outcomes following institutional deprivation and, (iii) add to our understanding of environmental determinants of sADHD.

Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction.

BACKGROUND: The appropriate treatment for patients in whom reperfusion fails to occur after thrombolytic therapy for acute myocardial infarction remains unclear. There are few data comparing emergency percutaneous coronary intervention (rescue PCI) with conservative care in such patients, and none comparing rescue PCI with repeated thrombolysis. METHODS: We conducted a multicenter trial in the United Kingdom involving 427 patients with ST-segment elevation myocardial infarction in whom reperfusion failed to occur (less than 50 percent ST-segment resolution) within 90 minutes after thrombolytic treatment. The patients were randomly assigned to repeated thrombolysis (142 patients), conservative treatment (141 patients), or rescue PCI (144 patients). The primary end point was a composite of death, reinfarction, stroke, or severe heart failure within six months. RESULTS: The rate of event-free survival among patients treated with rescue PCI was 84.6 percent, as compared with 70.1 percent among those receiving conservative therapy and 68.7 percent among those undergoing repeated thrombolysis (overall P=0.004). The adjusted hazard ratio for the occurrence of the primary end point for repeated thrombolysis versus conservative therapy was 1.09 (95 percent confidence interval, 0.71 to 1.67; P=0.69), as compared with adjusted hazard ratios of 0.43 (95 percent confidence interval, 0.26 to 0.72; P=0.001) for rescue PCI versus repeated thrombolysis and 0.47 (95 percent confidence interval, 0.28 to 0.79; P=0.004) for rescue PCI versus conservative therapy. There were no significant differences in mortality from all causes. Nonfatal bleeding, mostly at the sheath-insertion site, was more common with rescue PCI. At six months, 86.2 percent of the rescue-PCI group were free from revascularization, as compared with 77.6 percent of the conservative-therapy group and 74.4 percent of the repeated-thrombolysis group (overall P=0.05). CONCLUSIONS: Event-free survival after failed thrombolytic therapy was significantly higher with rescue PCI than with repeated thrombolysis or conservative treatment. Rescue PCI should be considered for patients in whom reperfusion fails to occur after thrombolytic therapy.

Outcome after pulmonary radiotherapy in Wilms' tumor patients with pulmonary metastases at diagnosis: a UK Children's Cancer Study Group, Wilms' Tumour Working Group Study.

PURPOSE: To evaluate the effect of whole lung radiotherapy on event-free and overall survival of children with Stage IV Wilms' tumor with pulmonary metastases at diagnosis and to ascertain factors that may have led to the decision to withhold radiotherapy. METHODS AND MATERIALS: We compared recurrence and mortality risks of patients with pulmonary metastases at diagnosis enrolled in the UKW2 and UKW3 clinical trials (1986-2001) according to treatment with pulmonary radiotherapy. RESULTS: Of 102 eligible patients (43 patients in UKW2 and 59 patients in UKW3), 72 (71%) received pulmonary radiotherapy; 30 (29%) did not. After a median follow-up of 9.3 years (range, 0.6-14.1 years), event-free survival was 79.2% (95% confidence interval [CI], 67.8-86.9%) in patients who received pulmonary radiotherapy compared with 53.3% (95% CI, 34.3-69.1%) in patients who did not receive it (p = 0.006), with a hazard ratio of 2.66 (95% CI, 1.28-5.52; p = 0.009). There was no difference in overall survival (84.7% [95% CI, 74.1-91.2%] vs. 73.2% [95% CI, 53.4-85.6%], respectively; p = 0.157). Pulmonary radiotherapy reduced the chance of lung relapse (8.3% vs. 23.3%; p = 0.039). The omission of radiotherapy did not seem to be consistently associated with any specific clinical or radiologic features. CONCLUSIONS: Outcome may be compromised if pulmonary radiotherapy is omitted in children with Wilms' tumor with pulmonary metastases. There was a significant effect on event-free survival; the risk of an event, particularly lung recurrence, was increased nearly threefold. Strategies for selection of children for avoidance of pulmonary irradiation need to be developed in a controlled fashion.

Emotional difficulties in early adolescence following severe early deprivation: findings from the English and Romanian adoptees study.

The study assessed conduct and emotional difficulties in a group of Romanian adoptees at age 11, and serves as a follow-up to assessments made when the children were 6 years old. It was found that there was a significant increase in emotional difficulties, but not conduct problems, for the Romanian sample since age 6. It was also found that emotional difficulty was significantly more prevalent at age 11 in the Romanian group than in a within-UK adoptee group. Emotional difficulties in the Romanian adoptee group were found to be significantly and strongly related to previous deprivation-specific problems (disinhibited attachment, cognitive impairment, inattention/overactivity and quasi-autism); however, the presence of such early problems did not account fully for the onset of later emotional problems. Five contrasting hypotheses concerning possible mediators for later onset of emotional difficulties for the Romanian group were examined. No links were found to duration of deprivation or other deprivation-related indices, stresses/difficulties in the postadoption family environment, or educational attainment and self-esteem. There was some evidence that emotion recognition might play a role in the emergence of these problems, but other measures of social competence and theory of mind showed no associations with the onset of emotional problems.

Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence.

The current study examined the persistence and phenotypic presentation of inattention/overactivity (I/O) into early adolescence, in a sample of institution reared (IR) children adopted from Romania before the age of 43 months. Total sample comprised 144 IR and 21 non-IR Romanian adoptees, and a comparison group of 52 within-UK adoptees, assessed at ages 6 and 11 years. I/O was rated using Rutter Scales completed by parents and teachers. I/O continued to be strongly associated with institutional deprivation, with continuities between ages 6 and 11 outcomes. There were higher rates of deprivation-related I/O in boys than girls, and I/O was strongly associated with conduct problems, disinhibited attachment and executive function but not IQ more generally, independently of gender. Deprivation-related I/O shares many common features with ADHD, despite its different etiology and putative developmental mechanisms. I/O is a persistent domain of impairment following early institutional deprivation of 6 months or more, suggesting there may be a possible pathway to impairment through some form of neuro-developmental programming during critical periods of early development.