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Abstract Background Although the primary risk factors for developing oral cancers are well understood, less is known about the relationship among the secondary factors that may modulate the progression of oral cancers, such as high-risk human papillomavirus (HPV) infection and folic acid (FA) supplementation. This study examined high-risk HPV and FA supplementation effects, both singly and in combination, to modulate the proliferative phenotypes of the oral cancer cell lines CAL27, SCC25 and SCC15. Results Using a comprehensive series of integrated in vitro assays, distinct effects of HPV infection and FA supplementation were observed. Both high-risk HPV strains 16 and 18 induced robust growth-stimulating effects in CAL27 and normal HGF-1 cells, although strain-specific responses were observed in SCC25 and SCC15 cells. Differential effects were also observed with FA administration, which significantly altered the growth rate of the oral cancer cell lines CAL27, SCC15, and SCC25, but not HGF-1 cells. Unlike HPV, FA administration induced broad, general increases in cell viability among all cell lines that were associated with p53 mRNA transcriptional down-regulation. None of these cell lines were found to harbor the common C677T mutation in methylenetetrahydrofolate reductase (MTHFR), which can reduce FA availability and may increase oral cancer risk. Conclusion Increased FA utilization and DNA hypermethylation are common features of oral cancers, and in these cell lines, specifically. The results of this study provide further evidence that FA antimetabolites, such as Fluorouracil (f5U or 5-FU) and Raltitrexed, may be alternative therapies for tumors resistant to other therapies. Moreover, since the incidence of oral HPV infection has been increasing, and can influence oral cancer growth, the relationship between FA bioavailability and concomitant HPV infection must be elucidated. This study is among the first pre-clinical studies to evaluate FA- and HPV-induced effects in oral cancers, both separately and in combination, which provides additional rationale for clinical screening of HPV infection prior to treatment.

Background and Objectives: Previous research has been limited in the comprehensive study of associations between the use of individual antiseizure medications (ASMs) in pregnancy and specific groups of birth defects, and systematic reviews and meta-analyses on the topic are limited by pooled samples and study designs. This study investigated birth defects related to ASM use in pregnancy in children born to women with epilepsy in Sweden over 20 years., Methods: We used data from Swedish national registers to follow a cohort of 17,996 children born to women diagnosed with epilepsy any time before conception in Sweden from 1996 to 2016, following them through 2017. We examined maternal-reported use of the 4 most commonly reported ASMs: lamotrigine (n = 2,148, 11.9%), carbamazepine (n = 1,940, 10.8%), valproic acid (n = 1,043, 5.80%), and levetiracetam (n = 587, 3.26%). We identified birth defects using diagnoses recorded at the time of discharge from the hospital and inpatient and outpatient diagnoses recorded in the first year of life. Models were estimated in a stepped fashion: unadjusted, adjusted for covariates, among a subcohort born to women diagnosed 10 years before conception (n = 14,586), and restricted to monotherapy., Results: Valproic acid use in pregnancy had the strongest and most widespread associations with birth defects in children, with carbamazepine also having links to several birth defects, including respiratory system and genital organ defects. Lamotrigine use in pregnancy was associated with cleft lip/palate and chromosomal abnormalities. Levetiracetam was most often used with other ASMs and preliminarily associated with many birth defects., Discussion: Our findings support avoidance of valproic acid use in pregnancy whenever possible. Lamotrigine and carbamazepine may be safer alternatives. However, these medications were also associated with certain birth defects, including some not reported previously. We are among the first to examine the possible effects of levetiracetam use in pregnancy, though more research is needed to investigate this further., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Purpose: To evaluate the relative efficacy of peripheral defocus contact lenses (PDCLs) and orthokeratology (OK) in a real-world clinical population, and compare these results with previous randomised controlled clinical trials., Methods: Records from a university practice were reviewed to identify children who were treated with OK or PDCLs. The analysed sample contained 273 visits from 77 patients. Annualised rates of axial length (AL) progression were calculated and used as the response variable in both linear mixed-effects (LME) and nonlinear regression models., Results: On average, children were 10.7 years of age at baseline (p = 0.14 between treatments), and most patients were female. More Asian children wore OK lenses compared with PDCLs (p < 0.01). At baseline, children had ~3.00 D of myopia and 0.75 D of astigmatism in both treatment groups (p > 0.20 between treatments). LME regression models using only baseline covariates showed no evidence that the annualised change in AL differed between treatments, with or without the inclusion of age, race, sex, baseline AL or spherical equivalent refractive error. Across all possible subsets of models, age at baseline was the best predictor of annualised AL change. There was no statistical difference between parameters of an exponential decay model fitted within treatment using follow-up age as a time-varying predictor, indicating that the rate of annualised change in AL was similar for OK and PDCL., Conclusions: Retrospective analysis of real-world clinical data found no difference in annualised AL growth between PDCL and OK. Importantly, the AL progression from this clinical setting is consistent with that reported in randomised clinical trials. Therefore, continued research of real-world performance is warranted to understand the safety and efficacy of modern myopia control treatments in the broader population., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

Introduction: Research has consistently shown individuals with mental health conditions are more likely to be prescribed opioid analgesic medications and to engage in heavier utilization. However, it is unclear whether these findings apply to pregnant women., Study Design: We explored opioid analgesic prescription in 689,400 pregnancies occurring in Sweden between 2007 and 2013. We investigated prescription patterns across time and type of source clinic for any opioid analgesic and for strong and weak opioid analgesics. We further evaluated the extent to which receipt of opioid analgesic medications was associated with previous mental health diagnoses and prescriptions of other psychoactive medications., Results: The prevalence of pregnant women who filled prescriptions for opioid analgesics (4.5%) was relatively stable across the assessed years. However, among pregnant women who filled opioid analgesic prescriptions, there was a large increase in strong opioid analgesic prescriptions-from 6.1% in 2007 to 17.1% in 2013. The main source of opioid analgesic prescriptions were primary care and obstetrics and gynecology clinics-38.7% of all filled prescriptions originated from primary care providers and 25.3% from obstetrics and gynecology practitioners. Compared to pregnant women who did not fill any opioid analgesic prescriptions, those who did were more likely to have a wide range of preexisting mental health diagnoses (e.g. anxiety disorder odds ratio [OR] = 3.13, 95% confidence interval [CI]:2.98,3.29) and to utilize a wide range of other psychoactive medications (e.g. benzodiazepines OR = 4.26, 95% CI:4.10,4.43). Similarly, those who received strong opioids were more likely to have a wide range of mental health diagnoses and be prescribed a wide range of psychoactive medications compared to those who received weak opioids., Conclusions: These results highlight the need for physicians treating pregnant women and women of childbearing age for painful conditions to obtain detailed histories of mental health problems, screen for symptoms of mental health problems, and facilitate integrated care and evidence-based mental health interventions if needed.

Background and Objectives: To evaluate whether children born to women who use serotonergic antidepressants during pregnancy have higher risk of neonatal seizures and epilepsy., Methods: We used Swedish register-based data to examine associations between maternal reported use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in pregnancy and diagnosis of neonatal seizures or epilepsy in >1.2 million children. To account for systematic differences between exposed and unexposed children, we adjusted for a wide range of measured confounders. After first evaluating the role of maternal indication for SSRI/SNRI use (i.e., depression or anxiety) and parental epilepsy, we adjusted for remaining parental background factors (e.g., age, comorbidities, education, and family socioeconomic indices) and pregnancy-specific characteristics (e.g., maternal use of other psychotropic medications and tobacco smoking in early pregnancy)., Results: Compared with all other children, children of women who reported use of SSRI/SNRI in pregnancy had an elevated risk of neonatal seizures and epilepsy (risk ratio [RR] 1.41, 95% CI 1.03-1.94; hazard ratio [HR] 1.21, 95% CI 1.03-1.43, respectively). The estimates of association were attenuated by adjustment for maternal indications for SSRI/SNRI use (RR 1.30, 95% CI 0.94-1.80; HR 1.13, 95% CI 0.95-1.33), but not by additional adjustment for parental history of epilepsy. Full adjustment for all measured parental and pregnancy-specific factors resulted in substantial attenuation of the remaining associations (RR 1.10, 95% CI 0.79-1.53; HR 0.96, 95% CI 0.81-1.14)., Discussion: We found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children's risk for neonatal seizures or epilepsy., Classification of Evidence: This study provides Class II evidence that exposure to SSRIs/SNRIs in the first trimester of pregnancy is not associated with an increased incidence of neonatal seizures/epilepsy., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Abstract: Efforts to reduce opioid-related harms have decreased opioid prescription but have provoked concerns about unintended consequences, particularly for long-term opioid therapy (LtOT) recipients. Research is needed to address the knowledge gap regarding how risk of substance-related morbidity changes across LtOT and its discontinuation. This study used nationwide commercial insurance claims data and a within-individual design to examine associations of LtOT dose and discontinuation with substance-related morbidity. We identified 194,839 adolescents and adults who initiated opioid prescription in 2010 to 2018 and subsequently received LtOT. The cohort was followed for a median of 965 days (interquartile range, 525-1550), of which a median of 176 days (119-332) were covered by opioid prescription. During follow-up, there were 17,582 acute substance-related morbidity events, defined as claims for emergency visits, inpatient hospitalizations, and ambulance transportation with substance use disorder or overdose diagnoses. Relative to initial treatment, risk was greater within individual during subsequent periods of >60 to 120 (adjusted odds ratio [OR], 1.29; 95% CI, 1.12 to 1.49) and >120 (OR, 1.48; 95% CI, 1.24-1.76) daily morphine milligram equivalents. Risk was also greater during days 1 to 30 after discontinuations than during initial treatment (OR, 1.19; 95% CI, 1.05-1.35). However, it was no greater than during the 30 days before discontinuations, indicating that the risk may not be wholly attributable to discontinuation itself. Results were supported by a negative control pharmacotherapy analysis and additional sensitivity analyses. They suggest that LtOT recipients may experience increased substance-related morbidity risk during treatment subsequent to initial opioid prescription, particularly in periods involving higher doses., (Copyright © 2021 International Association for the Study of Pain.)

Background and Objectives: Opioids are involved in an increasing proportion of suicide deaths. This study examined the association between opioid analgesic prescription initiation and suicidal behavior among young people., Methods: We analyzed Swedish population-register data on 1 895 984 individuals ages 9 to 29 years without prior recorded opioid prescriptions. We identified prescriptions dispensed from January 2007 onward and diagnosed self-injurious behavior and death by suicide through December 2013. We first compared initiators with demographically matched noninitiators. To account for confounding, we applied an active comparator design, which examined suicidal behavior among opioid initiators relative to prescription nonsteroidal antiinflammatory drug (NSAID) initiators while inverse-probability-of-treatment weighting with individual and familial covariates., Results: Among the cohort, 201 433 individuals initiated opioid prescription. Relative to demographically matched noninitiators, initiators (N = 180 808) had more than doubled risk of incident suicidal behavior (hazard ratio = 2.64; 95% confidence interval [CI], 2.47-2.81). However, in the active comparator design, opioid initiators (N = 86 635) had only 19% relatively greater risk of suicidal behavior compared with NSAID initiators (N = 255 096; hazard ratio = 1.19; 95% CI,: 1.11-1.28), corresponding to a weighted 5-year cumulative incidence of 2.2% (95% CI, 2.1-2.4) for opioid and 1.9% (95% CI, 1.9-2.0) for NSAID initiators. Most sensitivity analyses produced comparable results., Conclusions: Opioid initiation may make only a small contribution to the elevated risk of suicidal behavior among young people receiving pharmacologic pain management. In weighing benefits and harms of opioid initiation, our results suggest that increased risk of suicidal behavior may not be a major concern., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Larsson has served as a speaker for Evolan and Shire and has received research grants from Shire, all outside the submitted work. The authors report no other conflicts of interest., (Copyright © 2022 by the American Academy of Pediatrics.)

In a sample of over one million Swedish first-born offspring, we examined associations between early maternal age at first childbirth (MAFC; i.e., < 20 and 20-24 vs 25-29 years) and offspring non-accidental deaths, accidental deaths, deaths by suicide, non-fatal accidents, and suicide attempts. We included year of birth and several maternal and paternal characteristics as covariates and conducted maternal cousin comparisons to adjust for unmeasured confounding. Early MAFC (e.g., teenage childbearing) was associated with all outcomes, with the most pronounced risk elevation for accidental deaths [Hazard Ratio (HR) < 20 2.50, 95% confidence interval (CI) 2.23, 2.80], suicides (HR < 20 2.08, 95% CI 1.79, 2.41), and suicide attempts (HR < 20 2.85, 95% CI 2.71, 3.00). Adjusting for covariates and comparing cousins greatly attenuated associations (e.g., accidental deaths HR < 20 1.61, 95% CI 1.22, 2.11; suicides HR < 20 1.01, 95% CI 0.69, 1.47; and suicide attempts HR < 20 1.35, 95% CI 1.19, 1.52). A similar pattern emerged for non-accidental deaths and non-fatal accidents. Therefore, results indicated maternal background factors may be largely responsible for observed associations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pregnant women with painful conditions often have mental health problems, including depression and anxiety. Co-morbid conditions may cause pregnant women to use multiple medications, although safety of such practice is poorly understood., Objectives: We investigated the influence of combined prescriptions of opioid analgesics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy on two adverse birth outcomes., Methods: We analysed Swedish population-based births (n = 688 914) between 2007 and 2013. Using national registers, we obtained data on filled medication prescriptions, birth outcomes, and a wide range of parental characteristics. We estimated preterm birth and small-for-gestational-age risk following independent or combined prescriptions of the two medications compared with no filled prescriptions for either medication. We adjusted for confounders using inverse probability of treatment weights., Results: After adjusting for confounders, preterm birth risk was higher among women with opioid analgesic prescriptions only (5.9%; risk ratio [RR] 1.27, 95% confidence interval [CI] 1.22, 1.33), SSRIs only (6.2%; RR 1.34, 95% CI 1.27, 1.42), and both medications (7.8%; RR 1.70, 95% CI 1.47, 1.96) compared with unexposed women (4.6%). The interaction between the medications on preterm birth was small (risk difference [RD] 0.4%, 95% CI -0.8%, 1.6%); relative excess risk due to interaction [RERI] 0.09, 95% CI -0.17, 0.34; RR 1.00, 95% CI 0.85, 1.17). For small for gestational age, risk was approximately 2% across all groups, and there was no interaction between the medications (RD 0.3%, 95% CI -0.4%, 1.1%); RERI 0.15, 95% CI -0.16, 0.47; RR 1.15, 95% CI 0.87, 1.52)., Conclusions: Compared with unexposed pregnancies, those with either medication alone had a small increased risk for preterm birth but no increased risk for small for gestational age. The magnitude of associations with combined exposure to both medications were not greater than the sum of the associations with each medication considered individually., (© 2020 John Wiley & Sons Ltd.)

Previous research assessing consequences of interpregnancy intervals (IPIs) on child development is mixed. Utilizing a population-based US sample (n=5,339), we first estimated the associations between background characteristics (e.g., sociodemographic and maternal characteristics) and short (≤ 1 year) and long (> 3 years) IPI. Then, we estimated associations between IPI and birth outcomes, infant temperament, cognitive ability, and externalizing symptoms. Several background characteristics, such as maternal age at childbearing and previous pregnancy loss, were associated with IPI, indicating research on the putative effects of IPI must account for background characteristics. After covariate adjustment, short IPI was associated with poorer fetal growth and long IPI was associated with lower infant activity level; however, associations between short and long IPI and the other outcomes were neither large nor statistically significant. These findings indicate that rather than intervening to modify IPI, at-risk families may benefit from interventions aimed at other modifiable risk factors., Competing Interests: All authors have no conflicts of interest.

Objective: To determine whether children born to women who use antiseizure medications (ASMs) during pregnancy have higher risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) independent of confounding factors., Methods: We used Swedish register data (n = 14,614 children born 1996-2011 and followed up through 2013) to examine associations in children of women with epilepsy, using the largest sample to date and adjusting for a range of measured confounders. We examined maternal-reported first-trimester use of any ASM (22.7%) and the 3 most commonly reported individual drugs (valproic acid 4.8%, lamotrigine 6.8%, and carbamazepine 9.7%). We identified ASD with ICD-10 diagnoses and ADHD with ICD-10 diagnoses or filled prescriptions of ADHD medication., Results: Examination of individual drugs revealed that after adjustment for confounding, use of valproic acid was associated with ASD (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.53-3.47) and ADHD (HR 1.74, 95% CI 1.28-2.38). Whereas a small, nonstatistically significant association with ASD (HR 1.25, 95% CI = 0.88-1.79) and ADHD (HR 1.18, 95% CI 0.91-1.52) remained for reported use of carbamazepine, confounding explained all of the associations with lamotrigine (HR ASD 0.86, 95% CI 0.67-1.53; HR ADHD 1.01, 95% CI 0.67-1.53)., Conclusions: We found no evidence of risk related to exposure to lamotrigine, whereas we observed elevated risk of ASD and ADHD related to maternal use of valproic acid. Associations with carbamazepine were weak and not statistically significant. Our findings add to a growing body of evidence that suggests that certain ASMs may be safer than others in pregnancy., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: Concerns about adverse outcomes associated with opioid analgesic prescription have led to major guideline and policy changes. Substantial uncertainty remains, however, regarding the association between opioid prescription initiation and increased risk of subsequent substance-related morbidity., Objective: To examine the association of opioid initiation among adolescents and young adults with subsequent broadly defined substance-related morbidity., Design, Setting, and Participants: This cohort study analyzed population-register data from January 1, 2007, to December 31, 2013, on Swedish individuals aged 13 to 29 years by January 1, 2013, who were naive to opioid prescription. To account for confounding, the analysis compared opioid prescription recipients with recipients of nonsteroidal anti-inflammatory drugs as an active comparator, compared opioid-recipient twins and other multiple birth individuals with their nonrecipient co-multiple birth offspring (co-twin control), examined dental prescription as a specific indication, and included individual, parental, and socioeconomic covariates. Data were analyzed from March 30, 2019, to January 22, 2020., Exposures: Opioid prescription initiation, defined as first dispensed opioid analgesic prescription., Main Outcomes and Measures: Substance-related morbidity, assessed as clinically diagnosed substance use disorder or overdose identified from inpatient or outpatient specialist records, substance use disorder or overdose cause of death, dispensed pharmacotherapy for alcohol use disorder, or conviction for substance-related crime., Results: Among the included cohort (n = 1 541 862; 793 933 male [51.5%]), 193 922 individuals initiated opioid therapy by December 31, 2013 (median age at initiation, 20.9 years [interquartile range, 18.2-23.6 years]). The active comparator design included 77 143 opioid recipients without preexisting substance-related morbidity and 229 461 nonsteroidal anti-inflammatory drug recipients. The adjusted cumulative incidence of substance-related morbidity within 5 years was 6.2% (95% CI, 5.9%-6.5%) for opioid recipients and 4.9% (95% CI, 4.8%-5.1%) for nonsteroidal anti-inflammatory drug recipients (hazard ratio, 1.29; 95% CI, 1.23-1.35). The co-twin control design produced comparable results (3013 opioid recipients and 3107 nonrecipients; adjusted hazard ratio, 1.43; 95% CI, 1.02-2.01), as did restriction to analgesics prescribed for dental indications and additional sensitivity analyses., Conclusions and Relevance: Among adolescents and young adults analyzed in this study, initial opioid prescription receipt was associated with an approximately 30% to 40% relative increase in risk of subsequent substance-related morbidity in multiple designs that adjusted for confounding. These findings suggest that this increase may be smaller than previously estimated in some other studies.

We examined the extent to which genetic factors shared across generations, measured covariates, and environmental factors associated with parental suicidal behavior (suicide attempt or suicide) account for the association between parental and offspring suicidal behavior. We used a Swedish cohort of 2,762,883 offspring born 1973-2001. We conducted two sets of analyses with offspring of half- and full-siblings: (1) quantitative behavior genetic models analyzing maternal suicidal behavior and (2) fixed-effects Cox proportional hazard models analyzing maternal and paternal suicidal behavior. The analyses also adjusted for numerous measured covariates (e.g., parental severe mental illness). Quantitative behavior genetic analyses found that 29.2% (95% confidence interval [CI], 5.29, 53.12%) of the intergenerational association was due to environmental factors associated with exposure to maternal suicidal behavior, with the remainder due to genetic factors. Statistical adjustment for parental behavioral health problems partially attenuated the environmental association; however, the results were no longer statistically significant. Cox hazard models similarly found that offspring were at a 2.74-fold increased risk [95% CI, 2.67, 2.83]) of suicidal behavior if their mothers attempted/died by suicide. After adjustment for familial factors and measured covariates, associations attenuated but remained elevated for offspring of discordant half-siblings (HR, 1.57 [95% CI, 1.45, 1.71]) and full-siblings (HR, 1.62 [95% CI, 1.57, 1.67]). Cox hazard models demonstrated a similar pattern between paternal and offspring suicidal behavior. This study found that the intergenerational transmission of suicidal behavior is largely due to shared genetic factors, as well as factors associated with parental behavioral health problems and environmental factors associated with parental suicidal behavior.

Background: Published research on prescribed opioid analgesic (POA) use during pregnancy and birth outcomes is limited in scope and has not adequately adjusted for potential confounding factors. To help address these gaps, we estimated associations between maternal POAs during pregnancy and two adverse birth outcomes using a large population-based dataset, multiple definitions of POA exposure, and several methods to evaluate the influence of both measured and unmeasured confounding factors., Methods and Findings: We obtained data by linking information from several Swedish registers and conducted a retrospective cohort study on a population-based sample of 620,458 Swedish births occurring between 2007 and 2013 (48.6% female; 44.4% firstborn). We evaluated associations between prenatal POA exposure and risk for preterm birth (PTB; <37 gestational weeks) and small for gestational age (SGA; birth weight 2 standard deviations below the expected weight for gestational age or lower). We evaluated the influence of confounding by adjusting for a wide range of measured covariates while comparing exposed and unexposed infants. Additionally, we adjusted for unmeasured confounding factors by using several advanced epidemiological designs. Infants exposed to POAs anytime during pregnancy were at increased risk for PTB compared with unexposed infants (6.4% exposed versus 4.4% unexposed; adjusted odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.31-1.45, p < 0.001). This association was attenuated when we compared POA-exposed infants with acetaminophen-exposed infants (OR = 1.18, 95% CI 1.07-1.30, p < 0.001), infants born to women who used POAs before pregnancy only (OR = 1.05, 95% CI 0.96-1.14, p = 0.27), and unexposed siblings (OR = 0.99, 95% CI 0.85-1.14, p = 0.92). We also evaluated associations with short-term versus persistent POA use during pregnancy and observed a similar pattern of results, although the magnitudes of associations with persistent exposure were larger than associations with any use or short-term use. Although short-term use was not associated with SGA (adjusted ORsingle-trimester = 0.95, 95% CI 0.87-1.04, p = 0.29), persistent use was associated with increased risk for SGA (adjusted ORmultiple-trimester = 1.40, 95% CI 1.17-1.67, p < 0.001) compared with unexposed infants. The association with persistent exposure was attenuated when we used alternative comparison groups (e.g., sibling comparison OR = 1.22, 95% CI 0.60-2.48, p = 0.58). Of note, our study had limitations, including potential bias from exposure misclassification, an inability to adjust for all sources of confounding, and uncertainty regarding generalizability to countries outside of Sweden., Conclusions: Our results suggested that observed associations between POA use during pregnancy and risk of PTB and SGA were largely due to unmeasured confounding factors, although we could not rule out small independent associations, particularly for persistent POA use during pregnancy., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PDQ declared that research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under award number R00DA040727; BMD declared that he has received grants from NIH to support the work; HL reported having served as a speaker for Eli Lilly and Shire and receiving a research grant from Shire, all outside the submitted work; and PL reported having served as a speaker for Medice. The authors have declared that no other competing interests exist.

There is evidence of greater opioid prescription to individuals in the United States with mental health conditions. Whether these associations generalize beyond the US prescription environment and to familial mental health and socioeconomic status (SES) has not been examined comprehensively. This study estimated associations of diverse preexisting mental health diagnoses, parental mental health history, and SES in childhood with opioid analgesic prescription patterns nationwide in Sweden. Using register-based data, we identified 5,071,193 (48.4% female) adolescents and adults who were naive to prescription opioid analgesics and followed them from 2007 to 2014. The cumulative incidence of any dispensed opioid analgesic within 3 years was 11.4% (95% CI, 11.3%-11.4%). Individuals with preexisting self-injurious behavior, as well as opioid and other substance use, attention-deficit/hyperactivity, depressive, anxiety, and bipolar disorders had greater opioid therapy initiation rates than did individuals without the respective conditions (hazard ratios from 1.24 [1.20-1.27] for bipolar disorder to 2.12 [2.04-2.21] for opioid use disorder). Among 1,298,083 opioid recipients, the cumulative incidence of long-term opioid therapy (LTOT) was 7.6% (7.6%-7.7%) within 3 years of initiation. All mental health conditions were associated with greater LTOT rates (hazard ratios from 1.66 [1.56-1.77] for bipolar disorder to 3.82 [3.51-4.15] for opioid use disorder) and were similarly associated with concurrent benzodiazepine-opioid therapy. Among 1,482,462 adolescents and young adults, initiation and LTOT rates were greater for those with parental mental health history or lower childhood SES. Efforts to understand and ameliorate potential adverse effects of opioid analgesics must account for these patterns.

Significance: Measurement of ocular aberrations is a critical component of many optical corrections., Purpose: This study examines the accuracy and repeatability of a newly available high-resolution pyramidal wavefront sensor-based aberrometer (Osiris by Costruzione Strumenti Oftalmici, Firenze, Italy)., Methods: An engineered model eye and a dilated presbyopic eye were used to assess accuracy and repeatability of aberration measurements after systematic introduction of lower- and higher-order aberrations with calibrated trial lenses (sphere +10.00 to -10.00 D, and astigmatic -4.00 and -2.00 D with axis 180, 90, and 45°) and phase plates (-0.57 to 0.60 μm of Seidel spherical aberration defined over a 6-mm pupil diameter). Osiris aberration measurements were compared with those acquired on a previously calibrated COAS-HD aberrometer for foveal and peripheral optics both with and without multizone dual-focus contact lenses. The impact of simulated axial and lateral misalignment was evaluated., Results: Root-mean-square errors for paraxial sphere (corneal plane), cylinder, and axis were, respectively, 0.07, 0.11 D, and 1.8° for the engineered model and 0.15, 0.26 D, and 2.7° for the presbyopic eye. Repeatability estimates (i.e., standard deviation of 10 repeat measures) for the model and presbyopic eyes were 0.026 and 0.039 D for spherical error. Root-mean-square errors of 0.01 and 0.02 μm, respectively, were observed for primary spherical aberration and horizontal coma (model eye). Foveal and peripheral measures of higher- and lower-order aberrations measured with the Osiris closely matched parallel data collected with the COAS-HD aberrometer both with and without dual-focus zonal bifocal contact lenses. Operator errors of focus and alignment introduced changes of 0.018 and 0.02 D/mm in sphere estimates., Conclusions: The newly available clinical pyramidal aberrometer provided accurate and repeatable measures of lower- and higher-order aberrations, even in the challenging but clinically important cases of peripheral retina and multifocal optics.

Background: Maternal infection during pregnancy (IDP) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, infection is associated with social adversity, poor living conditions and other background familial factors. As such, there is a need to rule out whether the observed association between maternal IDP and ADHD might be attributed to such confounding., Methods: This nationwide population-based cohort study using a family-based, quasi-experimental design included 1,066,956 individuals born in Sweden between 1992 and 2002. Data on maternal IDP (bacterial or viral) requiring hospitalization and ADHD diagnosis in offspring were gathered from Swedish National Registers, with individuals followed up through the end of 2009. Ordinary and stratified Cox regression models were used for estimation of hazard ratios (HRs) and several measured covariates were considered. Cousin- and sibling-comparisons accounted for unmeasured genetic and environmental factors shared by cousins and siblings., Results: In the entire population, maternal IDP was associated with ADHD in offspring (HR = 2.31, 95% CI = 2.04-2.61). This association was attenuated when accounting for measured covariates (HR = 1.86, 95% CI = 1.65-2.10). The association was further attenuated when adjusting for unmeasured factors shared between cousins (HR = 1.52, 95% CI = 1.12-2.07). Finally, the association was fully attenuated in sibling comparisons (HR = 1.03, 95% CI = 0.76-1.41)., Conclusions: This study suggests that the association between maternal IDP and offspring ADHD is largely due to unmeasured familial confounding. Our results underscore the importance of adjusting for unobserved familial risk factors when exploring risk factors for ADHD., (© 2018 Association for Child and Adolescent Mental Health.)

Background: Causal interpretation of associations between short interpregnancy interval (the duration from the preceeding birth to the conception of the next-born index child) and the offspring's psychological and educational problems may be influenced by a failure to account for unmeasured confounding., Methods: Using population-based Swedish data from 1973-2009, we estimated the association between interpregnancy interval and outcomes [autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), severe mental illness, suicide attempt, criminality, substance-use problem and failing grades] while controlling for measured covariates. We then used cousin comparisons, post-birth intervals (the interval between the second- and third-born siblings to predict second-born outcomes) and sibling comparisons to assess the influence of unmeasured confounding. We included an exploratory analysis of long interpregnancy interval., Results: Interpregnancy intervals of 0-5 and 6-11 months were associated with higher odds of outcomes in cohort analyses. Magnitudes of association were attenuated following adjustment for measured covariates. Associations were eliminated for ADHD, severe mental illness and failing grades, but maintained magnitude for ASD, suicide attempt, criminality and substance-use problem in cousin comparisons. Post-birth interpregnancy interval and sibling comparisons suggested some familial confounding. Associations did not persist across models of long interpregnancy interval., Conclusions: Attenuation of the association in cousin comparisons and comparable post-birth interval associations suggests that familial genetic or environmental confounding accounts for a majority of the association for ADHD, severe mental illness and failing grades. Modest associations appear independently of covariates for ASD, suicide attempt, criminality and substance-use problem. Post-birth analyses and sibling comparisons, however, show some confounding in these associations.

Importance: Adults with mental health conditions are more likely than those without to receive long-term opioid therapy. Less is known about opioid therapy among adolescents, especially those with mental health conditions., Objective: To examine associations between preexisting mental health conditions and treatments and initiation of any opioid and long-term opioid therapy among adolescents., Design, Setting, and Participants: A cohort of 1 224 520 incident opioid recipients without cancer diagnoses aged 14 to 18 years at first receipt was extracted from nationwide commercial health care claims data from January 1, 2003, to December 31, 2014. Analysis was conducted from August 19, 2016, to November 16, 2017. Associations between preexisting mental health conditions and treatments and any opioid receipt were examined by comparing recipients with nonrecipients matched on sex, calendar year and years of age of first enrollment, and months of enrollment (prior to the index month for recipients, ever for nonrecipients). Associations between preexisting mental health conditions and treatments and subsequent long-term opioid therapy were examined among recipients with at least 6 months' follow-up using Cox proportional hazards regressions adjusted for demographics., Exposures: Mental health condition diagnoses and treatments recorded in inpatient, outpatient, and filled-prescription claims prior to opioid receipt., Main Outcomes and Measures: Opioid receipt, defined as any opioid analgesic prescription claim, and long-term opioid therapy, defined as more than 90 days' supply within a 6-month window having no gaps in supply of more than 32 days., Results: Of the 1 224 520 new opioid recipients included, the median age at first receipt was 17 years (interquartile range, 16-18 years), and 51.1% were female. Median follow-up after first receipt was 625 days (interquartile range, 255-1268 days). Adolescents with anxiety, mood, neurodevelopmental, sleep, and nonopioid substance use disorders and most mental health treatments were significantly more likely to receive any opioid (odds ratios from 1.13 [95% CI, 1.10-1.16] for nonopioid substance use disorders to 1.69 [95% CI, 1.58-1.81] for nonbenzodiazepine hypnotics). Among the 1 000 453 opioid recipients (81.7%) who had at least 6 months' follow-up, the cumulative incidence of long-term opioid therapy was 3.0 (95% CI, 2.8-3.1) per 1000 recipients within 3 years after first opioid receipt. All preexisting mental health conditions and treatments were strongly associated with higher rates of long-term opioid therapy (adjusted hazard ratios from 1.73 [95% CI 1.54-1.95] for attention-deficit/hyperactivity disorder to 8.90 [95% CI, 5.85-13.54] for opioid use disorder)., Conclusions and Relevance: Commercially insured adolescents with many types of preexisting mental health conditions and treatments were modestly more likely to receive any opioid and were substantially more likely to subsequently transition to long-term opioid therapy relative to those without, although overall rates of long-term opioid therapy were low.

Objective: To examine associations among interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors., Methods: In this prospective cohort study, we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months) and adverse birth outcomes (ie, preterm birth [less than 37 weeks of gestation], low birth weight [LBW; less than 2,500 g], small for gestational age [SGA; greater than 2 SDs below average weight for gestational age]). Analyses included cousin and sibling comparisons and postbirth intervals (ie, the interval between secondborn and thirdborn offspring predicting secondborn outcomes) to address unmeasured familial confounding., Results: Traditional cohort-wide analyses showed higher odds of preterm birth (adjusted odds ratio [OR] 1.51, 99% CI 1.39-1.63, 5.99% preterm births]) and LBW (adjusted OR 1.25, 99% CI 1.13-1.39, 3.32% LBW) after a short interpregnancy interval (0-5 months) compared with offspring born after an interpregnancy interval of 18-23 months (3.21% preterm births, 1.92% LBW). Except for preterm birth (adjusted OR 1.72, 99% CI 1.26-2.35), associations were attenuated in cousin comparisons. A small association between a short interpregnancy interval and preterm birth remained in sibling comparisons (adjusted OR 1.22, 99% CI 1.11-1.35), but associations with LBW (adjusted OR 0.83, 99% CI 0.74-0.94) and SGA (adjusted OR 0.74, 99% CI 0.64-0.85) reversed direction. For pregnancy intervals of 60 months or more, odds of preterm birth (adjusted OR 1.51, 99% CI 1.43-1.60, 5.07% preterm births), LBW (adjusted OR 1.61, 99% CI 1.50-1.73, 3.43% low-birth-weight births), and SGA (adjusted OR 1.54, 99% CI 1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Associations between long interpregnancy interval and adverse birth outcomes remained through cousin and sibling comparisons. Postbirth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals., Conclusion: Familial confounding explains most of the association between a short interpregnancy interval and adverse birth outcomes, whereas associations with long interpregnancy intervals were independent of measured and unmeasured factors.

Objective: Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events., Method: The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not., Results: In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women., Conclusions: These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

The current study examined associations between labor induction and both (1) offspring attention-deficit hyperactivity disorder (ADHD) diagnosis in a Swedish birth cohort born 1992-2005 (n = 1,085,008) and (2) indices of offspring low academic achievement in a sub-cohort born 1992-1997 (n = 489,196). Associations were examined in the entire sample (i.e., related and unrelated individuals) with adjustment for measured covariates and, in order to account for unmeasured confounders shared within families, within differentially exposed cousins and siblings. We observed an association between labor induction and offspring ADHD diagnosis and low academic achievement in the population. However, these associations were fully attenuated after adjusting for measured covariates and unmeasured factors that cousins and siblings share. The results suggest that observed associations between labor induction and ADHD and low academic achievement may be due to genetic and/or shared environmental factors that influence both mothers' risk of labor induction and offspring neurodevelopment.

Importance: Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness., Objective: To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs., Design, Setting, and Participants: This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design., Exposures: Maternal self-reported smoking during pregnancy, obtained from antenatal visits., Main Outcomes and Measures: Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using International Classification of Diseases codes for bipolar disorder and schizophrenia spectrum disorders., Results: Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses., Conclusions and Relevance: This population- and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.

Importance: Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding., Objective: To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems., Design, Setting, and Participants: This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations., Exposures: Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations., Main Outcomes and Measures: Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring., Results: Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons., Conclusions and Relevance: Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Background: Advanced paternal age at childbirth is associated with psychiatric disorders in offspring, including schizophrenia, bipolar disorder and autism. However, few studies have investigated paternal age's relationship with eating disorders in offspring. In a large, population-based cohort, we examined the association between paternal age and offspring eating disorders, and whether that association remains after adjustment for potential confounders (e.g. parental education level) that may be related to late/early selection into fatherhood and to eating disorder incidence., Method: Data for 2 276 809 individuals born in Sweden 1979-2001 were extracted from Swedish population and healthcare registers. The authors used Cox proportional hazards models to examine the effect of paternal age on the first incidence of healthcare-recorded anorexia nervosa (AN) and all eating disorders (AED) occurring 1987-2009. Models were adjusted for sex, birth order, maternal age at childbirth, and maternal and paternal covariates including country of birth, highest education level, and lifetime psychiatric and criminal history., Results: Even after adjustment for covariates including maternal age, advanced paternal age was associated with increased risk, and younger paternal age with decreased risk, of AN and AED. For example, the fully adjusted hazard ratio for the 45+ years (v. the 25-29 years) paternal age category was 1.32 [95% confidence interval (CI) 1.14-1.53] for AN and 1.26 (95% CI 1.13-1.40) for AED., Conclusions: In this large, population-based cohort, paternal age at childbirth was positively associated with eating disorders in offspring, even after adjustment for potential confounders. Future research should further explore potential explanations for the association, including de novo mutations in the paternal germline.

There is growing evidence that opioid prescribing in the United States follows a pattern in which patients who are at the highest risk of adverse outcomes from opioids are more likely to receive long-term opioid therapy. These patients include, in particular, those with substance use disorders (SUDs) and other psychiatric conditions. This study examined health insurance claims among 10,311,961 patients who filled prescriptions for opioids. Specifically, we evaluated how opioid receipt differed among patients with and without a wide range of preexisting psychiatric and behavioral conditions (ie, opioid and nonopioid SUDs, suicide attempts or other self-injury, motor vehicle crashes, and depressive, anxiety, and sleep disorders) and psychoactive medications (ie, antidepressants, benzodiazepines, hypnotics, mood stabilizers, antipsychotics, and medications used for SUD, tobacco cessation, and attention-deficit/hyperactivity disorder). Relative to those without, patients with all assessed psychiatric conditions and medications had modestly greater odds of subsequently filling prescriptions for opioids and, in particular, substantially greater risk of long-term opioid receipt. Increases in risk for long-term opioid receipt in adjusted Cox regressions ranged from approximately 1.5-fold for prior attention-deficit/hyperactivity disorder medication prescriptions (hazard ratio [HR] = 1.53; 95% confidence interval [CI], 1.48-1.58) to approximately 3-fold for prior nonopioid SUD diagnoses (HR = 3.15; 95% CI, 3.06-3.24) and nearly 9-fold for prior opioid use disorder diagnoses (HR = 8.70; 95% CI, 8.20-9.24). In sum, we found evidence of greater opioid receipt among commercially insured patients with a breadth of psychiatric conditions. Future studies assessing behavioral outcomes associated with opioid prescribing should consider preexisting psychiatric conditions., Competing Interests: The authors report no conflicts of interest.

Importance: Induction of labor is a frequently performed obstetrical intervention. It would thus be of great concern if reported associations between labor induction and offspring risk of autism spectrum disorders (ASD) reflected causal influence., Objective: To assess the associations of labor induction with ASD, comparing differentially exposed relatives (siblings and cousins discordant for induction)., Design, Setting, and Participants: Follow-up of all live births in Sweden between 1992 and 2005, defined in the Medical Birth Register. The register was linked to population registers of familial relations, inpatient and outpatient visits, and education records. Diagnoses of ASD were from 2001 through 2013, and data were analyzed in the 2015-2016 year., Exposures: Induction of labor., Main Outcomes and Measures: Autism spectrum disorders identified by diagnoses from inpatient and outpatient records between 2001 and 2013. Hazard ratios (HRs) quantified the association between labor induction and offspring ASD. In addition to considering a wide range of measured confounders, comparison of exposure-discordant births to the same woman allowed additional control for all unmeasured factors shared by siblings., Results: The full cohort included 1 362 950 births, of which 22 077 offspring (1.6%) were diagnosed with ASD by ages 8 years through 21 years. In conventional models of the full cohort, associations between labor induction and offspring ASD were attenuated but remained statistically significant after adjustment for measured potential confounders (HR, 1.19; 95% CI, 1.13-1.24). When comparison was made within siblings whose births were discordant with respect to induction, thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD (HR, 0.99; 95% CI, 0.88-1.10)., Conclusions and Relevance: In this nationwide sample of live births we observed no association between induction of labor and offspring ASD within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor., Competing Interests: Disclosures: None reported.

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.

We examined associations of maternal age at childbearing (MAC) with gestational age and fetal growth (i.e., birth weight adjusting for gestational age), using two genetically informed designs (cousin and sibling comparisons) and data from two cohorts, a population-based Swedish sample and a nationally representative United States sample. We also conducted sensitivity analyses to test limitations of the designs. The findings were consistent across samples and suggested that, associations observed in the population between younger MAC and shorter gestational age were confounded by shared familial factors; however, associations of advanced MAC with shorter gestational age remained robust after accounting for shared familial factors. In contrast to the gestational age findings, neither early nor advanced MAC was associated with lower fetal growth after accounting for shared familial factors. Given certain assumptions, these findings provide support for a causal association between advanced MAC and shorter gestational age. The results also suggest that there are not causal associations between early MAC and shorter gestational age, between early MAC and lower fetal growth, and between advanced MAC and lower fetal growth.

Background: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors., Method: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings., Results: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement., Conclusions: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.

Background: It is unclear whether associations between fetal growth and psychiatric and socioeconomic problems are consistent with causal mechanisms., Aims: To estimate the extent to which associations are a result of unmeasured confounding factors using a sibling-comparison approach., Method: We predicted outcomes from continuously measured birth weight in a Swedish population cohort (n = 3 291 773), while controlling for measured and unmeasured confounding., Results: In the population, lower birth weight (⩽ 2500 g) increased the risk of all outcomes. Sibling-comparison models indicated that lower birth weight independently predicted increased risk for autism spectrum disorder (hazard ratio for low birth weight = 2.44, 95% CI 1.99-2.97) and attention-deficit hyperactivity disorder. Although attenuated, associations remained for psychotic or bipolar disorder and educational problems. Associations with suicide attempt, substance use problems and social welfare receipt, however, were fully attenuated in sibling comparisons., Conclusions: Results suggest that fetal growth, and factors that influence it, contribute to psychiatric and socioeconomic problems., (Royal College of Psychiatrists.)

Purpose: Parental severe mental illness (SMI) is associated with an increased risk of offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We conducted a study to examine the extent to which risk of preterm birth, low birth weight, and small for gestational age mediated this association., Methods: We obtained data on offspring born 1992-2001 in Sweden (n = 870,017) through the linkage of multiple population-based registers. We used logistic and Cox regression to assess the associations between parental SMI, adverse pregnancy outcomes, and offspring ASD and ADHD, as well as tested whether adverse pregnancy outcomes served as mediators., Results: After controlling for measured covariates, maternal and paternal SMI were associated with an increased risk for preterm birth, low birth weight, and gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were also associated with an increased risk of ASD and ADHD. We found that pregnancy outcomes did not mediate the association between parental SMI and offspring ASD and ADHD, as there was no substantial change in magnitude of the risk estimates after controlling for pregnancy outcomes., Conclusions: Parental SMI and adverse pregnancy outcomes appear to be independent risk factors for offspring ASD and ADHD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Importance: Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors., Objective: To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity., Design, Setting, and Participants: We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins., Exposure: Paternal age at childbearing., Main Outcomes and Measures: Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity., Results: In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings., Conclusions and Relevance: Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

Associations between low birth weight (≤2,500 g) and increased risk of mortality and morbidity provided the foundation for the "developmental origins of health and disease" hypothesis. Previous between-family studies could not control for unmeasured confounders. Therefore, we compared differentially exposed siblings to estimate the extent to which the associations were due to uncontrolled factors. Our population cohort included 3,291,773 persons born in Sweden from 1973 to 2008. Analyses controlled for gestational age, among other covariates, and considered birth weight as both an ordinal and a continuous variable. Outcomes included mortality after 1 year, cardiac-related death, hypertension, ischemic heart disease, pulmonary circulation problems, stroke, and type 2 diabetes mellitus. We fitted fixed-effects models to compare siblings and conducted sensitivity analyses to test alternative explanations. Across the population, the lower the birth weight, the greater the risk of mortality (e.g., cardiac-related death (low birth weight hazard ratio = 2.69, 95% confidence interval: 2.05, 3.53)) and morbidity (e.g., type 2 diabetes mellitus (low birth weight hazard ratio = 1.79, 95% confidence interval: 1.50, 2.14)) outcomes in comparison with normal birth weight. All associations were independent of shared familial confounders and measured covariates. Results emphasize the importance of birth weight as a risk factor for subsequent mortality and morbidity.

Background: Preconception, prenatal and postnatal maternal stress is associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt and completed suicide., Method: Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992-2000 for childhood outcomes and 2,155,221 offspring born 1973-1997 for adult outcomes with follow-up to 2009. Maternal stress was defined as death of a first-degree relative during (a) the 6 months before conception, (b) pregnancy or (c) the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HRs) in unadjusted and adjusted analyses., Results: Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third-trimester prenatal stress increased the risk of ASD [adjusted HR (aHR) 1.58, 95% confidence interval (CI) 1.15-2.17] and ADHD (aHR 1.31, 95% CI 1.04-1.66). First postnatal year stress increased the risk of offspring suicide attempt (aHR 1.13, 95% CI 1.02-1.25) and completed suicide (aHR 1.51, 95% CI 1.08-2.11). Bereavement stress during the second postnatal year increased the risk of ASD (aHR 1.30, 95% CI 1.09-1.55)., Conclusions: Further research is needed regarding associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases the risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases the risk of offspring suicide attempt, completed suicide and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.

Importance: Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm., Objective: To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity are the result of confounding factors by using a quasi-experimental design, the sibling-comparison approach, and by controlling for statistical covariates that varied within families., Design, Setting, and Participants: A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973 to 2008 (3,300,708 offspring of 1,736,735 mothers) and link them with multiple outcomes., Main Outcomes and Measures: Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, attention-deficit/hyperactivity disorder, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, and social welfare benefits) outcomes through 2009., Results: In the population, there was a dose-response relationship between early gestation and the outcome measures. For example, extreme preterm birth (23-27 weeks of gestation) was associated with infant mortality (odds ratio, 288.1; 95% CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95% CI, 2.6-4.0), low educational attainment (HR, 1.7; 1.5-2.0), and social welfare benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed-effects models., Conclusions and Relevance: The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome-specific. Associations between preterm birth and mortality and psychiatric morbidity are largely independent of shared familial confounds and measured covariates, consistent with a causal inference. However, some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits, are the result of confounding factors. The findings emphasize the importance of both reducing preterm birth and providing wraparound services to all siblings in families with an offspring born preterm.

Purpose: Electronic data capture is becoming increasingly common for collecting real-time patient responses. The purpose of this study was to investigate compliance with a daily electronic questionnaire regarding night-time contact lens visual performance., Method: Forty-eight subjects (34 females) were fit and dispensed two contralateral pairs of soft contact lenses (SCLs) for one week each. Subjects were sent a nightly e-mail at 8PM containing a secure, individualized link to an electronic questionnaire asking 30 questions of varying response styles (e.g., multiple choice, short answer, etc.) about SCL visual performance. Subjects were instructed to complete the questionnaire before going to bed., Results: The overall completion rate based on 676 electronic questionnaires was 95.1%. Of these, only 3.6% were completed late (<24h). The percentage of subjects completing all questionnaires was significantly higher on weekdays (96.5%; Sunday through Thursday) than on weekends (91.1%; Friday and Saturday). Fisher exact tests indicated no significant association with gender for either weekday (p=0.25) or weekend (p=0.73). Although odds ratio estimates suggested that participants 23 and older were more likely to complete the questionnaire (weekday: OR=4.39, p=0.10; weekend: OR=2.93, p=0.19), these associations did not reach statistical significance., Conclusions: E-mail based questionnaires provide an effective method for acquiring time specific responses, making them a viable clinical and research tool. The day(s) of the week on which assessments occur need to be strongly considered, as on-time compliance may be affected on weekend evenings, or possibly situations in which a typical schedule may not be followed., (Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Recent research suggests multizone/dual-focus (DF) lens corrections may aid in controlling the progression of myopia. Recently, such a soft contact lens has become commercially available in Hong Kong (MiSight, CooperVision). The purpose of the current study was to evaluate the visual acceptability of this new lens design., Methods: In a double-masked, randomized, crossover trial, 24 subjects (aged 18 to 25 years) wore MiSight contact lenses and Proclear Multifocal +2.00 diopters Add D (MF) soft contact lenses. Patient-reported outcomes (0 to 100 scale) and objective measures of visual performance were acquired for best-spectacle distance correction (BC) and with each contact lens after 1 week of daily use at HIHC (high illumination-high contrast) at distance and LILC (low illumination-low contrast) at distance, intermediate, and near., Results: There were no significant differences in HIHC distance acuity between BC and either the DF or MF lens and no difference between the DF and MF lenses. However, when measured under LILC, there were significant mean differences between each study lens and BC viewed at distance and intermediate. The LILC logMAR visual acuity was not significantly different between the DF and MF lenses at any viewing distance. Although average visual quality and ghosting ratings for both DF and MF study lenses were significantly lower than habitual under all conditions, there were no significant differences between the DF and MF lenses (p = 0.448)., Conclusions: Good acuity, similar to that attainable with typical MF lens correction, is attainable with a new contact lens designed to control myopia progression. However, like other contact lenses that contain multiple refractive zones, some decrease in visual performance may be experienced.

Teenage childbirth is a risk factor for poor offspring outcomes, particularly offspring antisocial behavior. It is not clear, however, if maternal age at first birth (MAFB) is causally associated with offspring antisocial behavior or if this association is due to selection factors that influence both the likelihood that a young woman gives birth early and that her offspring engage in antisocial behavior. The current study addresses the limitations of previous research by using longitudinal data from Swedish national registries and children of siblings and children of twins comparisons to identify the extent to which the association between MAFB and offspring criminal convictions is consistent with a causal influence and confounded by genetic or environmental factors that make cousins similar. We found offspring born to mothers who began childbearing earlier were more likely to be convicted of a crime than offspring born to mothers who delayed childbearing. The results from comparisons of differentially exposed cousins, especially born to discordant monozygotic twin sisters, provide support for a causal association between MAFB and offspring criminal convictions. The analyses also found little evidence for genetic confounding due to passive gene-environment correlation. Future studies are needed to replicate these findings and to identify environmental risk factors that mediate this causal association.

Context: Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring., Objective: To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design., Design: We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding., Setting: Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2)., Patients or Other Participants: Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1,187,360)., Main Outcome Measures: Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2)., Results: The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR](moderate), 1.32 [95% CI, 1.22-1.43]; HR(high), 1.33 [1.17-1.53]) to a narcotics-related conviction (HR(moderate), 2.23 [2.14-2.31]; HR(high), 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant., Conclusions: The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.

Purpose: Patient-reported subjective responses have become increasingly popular in describing contact lens visual performance and discriminating between designs. The purpose of the current study is to evaluate the ability of patient-reported measures of vision to quantify the perceptual effects of defocus., Methods: Ten young (18-35 years) subjects rated their subjective visual performance monocularly on 3 scales following wear of their optimal monocular distance correction and nine different blurring lenses (-0.50 to +1.50 in 0.25 D steps) in a trial frame. The three scales used were a 0-100 numeric rating scale (NRS), a 100 mm visual analog scale (VAS), and a 5 point ("Poor", "Fair", "Average", "Good", "Excellent") categorical rating scale (CRS)., Results: Mixed linear modeling results found no significant effects either for eye or trial number, but did find a significant effect due to blurring lens power (p<0.0001), with ratings decreasing with increasing levels of blur for all scales. Results were not significantly different between the NRS and VAS at any level of blur, with limits of agreement falling within 22% of the measurement scale. CRS ratings were about 15 units lower than the other scales on average, with limits of agreement that varied with lens power and were roughly 3 times as large. Across scale internal consistency was 0.94., Conclusions: The NRS and VAS yield virtually identical rating responses, but both differing slightly, however from the CRS. Each scale successfully discriminated levels of blur smaller than 0.25 D with only a single measurement., (Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background: Maternal smoking during pregnancy (SDP) has been studied extensively as a risk factor for adverse offspring outcomes and is known to co-occur with other familial risk factors. Accounting for general familial risk factors has attenuated associations between SDP and adverse offspring outcomes, and identifying these confounds will be crucial to elucidating the relationship between SDP and its psychological correlates., Method: The current study aimed to disentangle the relationship between maternal SDP and co-occurring risk factors (maternal criminal activity, drug problems, teen pregnancy, educational attainment, and cohabitation at childbirth) using a population-based sample of full- (n=206 313) and half-sister pairs (n=19 363) from Sweden. Logistic regression models estimated the strength of association between SDP and co-occurring risk factors. Bivariate behavioral genetic models estimated the degree to which associations between SDP and co-occurring risk factors are attributable to genetic and environmental factors., Results: Maternal SDP was associated with an increase in all co-occurring risk factors. Of the variance associated with SDP, 45% was attributed to genetic factors and 53% was attributed to unshared environmental factors. In bivariate models, genetic factors accounted for 21% (non-drug-, non-violence-related crimes) to 35% (drug-related crimes) of the covariance between SDP and co-occurring risk factors. Unshared environmental factors accounted for the remaining covariance., Conclusions: The genetic factors that influence a woman's criminal behavior, substance abuse and her offspring's rearing environment all influence SDP. Therefore, the intergenerational transmission of genes conferring risk for antisocial behavior and substance misuse may influence the associations between maternal SDP and adverse offspring outcomes.

Objectives: The defocused portion of the image obtained in wearers of bifocal and multifocal contact lenses often appears as a "ghost." Relatively few methods exist to quantify the ghosting perceived with lenses. The purpose of this study is to validate and implement a questionnaire to help patients quantify the ghost images perceived with bifocal or multifocal corrections., Methods: Ten subjects viewed simulated bifocal vision images displayed on a monitor. Images contained a focused and a defocused (ghost) component of a specific dimension (direction, position offset, intensity, and focus). Using a test card, the subjects identified the ghosting dimension level displayed on the monitor. An additional 54 presbyopic subjects wearing a multifocal correction monocularly viewed a well-focused stimulus and then compared the perceived image to that of the other well-corrected eye looking at the ghosting test card to quantify their visual experience of the 4 proposed ghosting dimensions., Results: Regardless of ghost letter size and orientation, subject responses were within 1 rating unit of expected on >95% of all trials for all 4 dimensions when asked to directly match a single dimension of ghosting. With bifocal images containing random amounts of these 4 dimensions most response errors were also within ± 1 unit. In presbyopes wearing a multifocal lens, the focus dimension was most strongly associated with overall ratings of ghosting., Conclusions: The subjects can accurately and reliably report on ghost intensity, focus, direction and position offset, and well-focused ghosts are most correlated with the overall perceptual saliency of ghosting.

Research has suggested that reduced working memory capacity plays a key role in disinhibited patterns of behavior associated with externalizing psychopathology. In this study, participants (N = 365) completed 2 versions of a go/no-go mixed-incentive learning task that differed in the relative frequency of monetary rewards and punishments for correct and incorrect active-approach responses, respectively. Using separate structural equation models for conventional (hit and false alarm rates) and signal detection theory (signal discriminability and response bias) performance indices, distinct roles for working memory capacity and changes in payoff structure were found. Specifically, results showed that (a) working memory capacity mediated the effects of externalizing psychopathology on false alarms and discriminability of go versus no-go signals; (b) these effects were not moderated by the relative frequency of monetary rewards and punishments; (c) the relative frequency of monetary rewards and punishments moderated the effects of externalizing psychopathology on hits and response bias for go versus no-go responses; and (d) these effects were not mediated by working memory capacity. The findings implicate distinct roles for reduced working memory capacity and poorly modulated active approach and passive avoidance in the link between externalizing psychopathology and behavioral disinhibition.

Increased discounting of delayed rewards may reflect a decision bias that contributes to excessive use of alcohol and more generally, to an impulsive, disinhibitory predisposition that is characterized by a preference for immediate over long-term rewards. The current study examined the association between delay discounting of rewards and the covariation among several types of disinhibitory problems that are often comorbid with alcohol dependence (AD). Lifetime problems with alcohol, marijuana, other drugs, childhood conduct disorder, and adult antisocial behavior were assessed in a sample of 426 young adults, 257 of whom had a lifetime diagnosis of AD. Higher delay discounting rates were associated with the covariation among all domains of disinhibitory problems and were not uniquely associated with any one domain. Higher delay discounting rates also were associated with lower intelligence, lower working memory capacity, and higher trait impulsivity. The results suggest that increased delay discounting of rewards may reflect aspects of a general vulnerability to externalizing, disinhibitory disorders.

Reduced executive cognitive ability is associated with alcohol dependence (AD) and other comorbid externalizing disorders. Working memory capacity, short-term memory, conditional associative learning, and intelligence were assessed in a sample (N = 477) with variation in lifetime histories of externalizing problems (conduct disorder, adult antisocial behavior, substance problems); this included a subsample (n = 285) with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnosis of AD. Individuals with both AD and a history of childhood conduct disorder (CCD) scored lower on cognitive measures compared to those with AD and no history of CCD. Structural equation models showed that reduced ability in all cognitive domains was predicted by a latent externalizing factor reflecting covariation among lifetime problems with alcohol, drugs, childhood conduct, and adult antisocial behavior and was not uniquely related to any one problem. Further, for those with AD, the externalizing factor was associated with reductions in all the domains of cognitive ability. The results suggest that the reduced executive cognitive ability observed in AD individuals is partly accounted for by a general latent externalizing factor rather than alcohol-related problems per se.

Background: Alcohol dependence (AD) is often comorbid with other disinhibitory disorders that are characterized by poor decision making and evidenced by disadvantageous strategies on laboratory tasks such as the Iowa Gambling Task (IGT). In this study, a variant of the IGT is used to examine specific mechanisms that may account for poor decision making on the task in AD both with and without comorbid psychopathology., Methods: The community sample (n = 428) included 134 young adult subjects with AD and a history of childhood conduct disorder (CCD), 129 with AD and no history of CCD, 60 with a history of CCD and no AD, and 105 controls. Lifetime histories of other disinhibitory problems (adult antisocial behavior, marijuana, and other drugs) and major depression also were assessed. A modified version of the IGT was used to estimate (i) insensitivity to future consequences (IFC), and (ii) preference for large versus small immediate reward decks (PLvS)., Results: Both AD and CCD were associated with greater IFC but not greater PLvS. Structural equation models (SEMs) indicated that IFC was associated with higher scores on a latent dimensional "disinhibitory disorders" factor representing the covariance among all lifetime measures of disinhibitory psychopathology, but was not directly related to any one disinhibitory disorder. SEMs also suggested that adult antisocial behavior was uniquely associated with a greater PLvS., Conclusions: Disadvantageous decision making on the IGT in those with AD and related disinhibitory disorders may reflect an IFC that is common to the covariance among these disorders but not unique to any one disorder.

This work was undertaken to answer the question, 'How does the speech audibility/fit-to-gain-target provided by compression change with number of channels?' For each of 957 audiograms and a given number of compression channels, the channel crossover frequencies were set either to maximize the SII (speech intelligibility index) for low- and high-level speech spectra, or to optimize the fit-to-gain targets from the Cambridge method for loudness equalization (CAMEQ). The audiograms comprised all common configurations, and losses ranged from mild to severe. Use of these computational procedures allowed the predicted, channel-number-based performance to be determined separately from the effects of other compression parameters. From one to five channels were sufficient to yield predicted speech recognition performance within 5% of maximum for 90% of the 'mild' and 'moderate' audiograms. Three to nine channels were necessary for the same level of predicted performance for 90% of the 'severe' audiograms. Four channels or fewer were sufficient to produce less than 5 dB rms error in fit to CAMEQ targets for 90% of all audiograms.

Aims: Research suggests that positive alcohol expectancies promote excessive alcohol use while negative alcohol expectancies discourage excessive alcohol use. Evidence suggests that disinhibitory characteristics, such as conduct disorder and impulsivity, are associated with a general neglect of long-term negative outcomes. This study assessed whether negative expectancies would be associated more strongly with lower levels of alcohol use for low- compared with high-impulsive individuals., Design: Positive and negative alcohol expectancies, alcohol use and impulsivity were assessed in a sample of 99 young adults with alcohol dependence (AD) and conduct disorder (CD), 77 with AD and no CD and 124 controls., Findings: AD/CD subjects had higher proximal (same day) and distal (next day) negative alcohol expectancies, even though they drank more alcohol, compared with AD-alone and control subjects. Distal negative expectancies were associated more strongly with lower levels of drinking for low-impulsive compared with high-impulsive subjects. Proximal negative expectancies were associated more strongly with higher alcohol consumption for high- versus low-impulsive subjects., Conclusions: Impulsivity and conduct disorder may be important factors in determining how much distal negative alcohol expectancies may discourage excessive alcohol consumption.