Positive predictive value of medical student specialty choices.

BACKGROUND: Although medical school programs oriented toward postgraduate specialty training have the potential to reduce the duration and cost of medical school for US medical students, success depends on the ability of students to predict their postgraduate specialties. It is clear that first-year choices are poorly predictive, but it is not known when predictions become sufficiently reliable to support specialty-oriented learning programs. We therefore examined the predictive value of specialty preferences expressed at the ends of the first, second and third years of medical school and asked whether concurrent expressions of confidence in choices improved predictive ability. We also investigated the possibility that discrepancies between predicted and actual postgraduate specialty training were related to scores on an examination of knowledge in basic biomedical sciences required for US medical school graduation (the United States Medical Licensing Examination (USLME) Step 1 examination). METHOD: We calculated positive and negative predictive values (PPV and NPV, respectively) for specialty choices and the sensitivity and specificity of asking for choices for 634 University of Colorado School of Medicine students who trained in 23 accredited residencies from 2011 through 2015. We examined the effect of confidence in first choices in 609 students, and in 334 students, sought an association between USMLE Step 1 scores and switching from postgraduate training specialties predicted at the end of year 2. RESULTS: The PPV of first choices improved from years 1 through 3. NPV was high throughout. PPVs of year 3 first choices ranged from 79% in Anesthesiology to 95% in Psychiatry. Expressions of confidence in first choices did not improve PPV. Sensitivity of asking for first choices increased with time; specificity was consistently high. USLME Step 1 scores were higher for students who ultimately trained in specialties more competitive than first-choice specialties at the end of year 2. CONCLUSIONS: Specialty-oriented learning programs during medical school must accommodate students who change career plans. The PPV of specialty first choices improves each year, but even year 3 predictions can be inaccurate with potential loss of students from specialty-specific programs. USMLE Step 1 scores appeared to affect career plans expressed at the end of year 2.

Cortisol during human fetal life: Characterization of a method for processing small quantities of newborn hair from 26 to 42 weeks gestation.

OBJECTIVE: Fetal cortisol may be reflected in hair collected shortly after birth. The objective of this study was to determine the range of human fetal hair cortisol concentrations (HCC) in live-born neonates using an approach for processing small quantities of hair. MATERIALS AND METHODS: Hair was cut on the day of birth from neonates and their mothers, born between 26 and 42 weeks gestational age (GA). HCC was determined by enzyme immunoassay. Maternal sociodemographics and birth data were collected. T-tests, ANOVA, Pearson correlation, and Wilcoxon Signed Rank test were used as appropriate. RESULTS: Ninety maternal and neonatal hair samples were cut from 79 term (T) and 11 preterm (PT) delivered pregnancies. All samples weighed ≥2.5 mg. Fetal HCC correlated with GA (r = .25, p = .02) and birth weight (r = .25, p = .03) and was lower in PT (4.3 ± .3 LN pg/mg) than T (5.3 ± .1, LN pg/mg, p < .001) neonates. No significant relationships were seen between fetal HCC and maternal characteristics or maternal HCC. Fetal HCC was significantly higher than maternal HCC. CONCLUSION: Fetal cortisol exposure was determined using this approach for processing small amounts of hair. Preterm neonates have significantly lower HCC than term neonates and fetal HCC is associated with GA at delivery and birth weight. Fetal HCC is significantly higher than maternal HCC cut on the same day. These data provide novel information on the intrauterine fetal cortisol environment.

Sleep Moderates and Mediates the Relationship Between Acculturation and Depressive Symptoms in Pregnant Mexican-American Women.

OBJECTIVE: Greater acculturation is associated with adverse perinatal outcomes in Mexican-American women, but the mechanisms by which acculturation influences perinatal outcomes are unclear. Pregnant acculturated Mexican-American women are more likely to engage in unhealthy prenatal behaviors relative to those less acculturated, including poor sleep. As sleep disruptions are associated with acculturation and negative perinatal outcomes, particularly maternal depression, alterations in sleep may adversely affect pregnant Mexican-American women. METHODS: Sixty pregnant women of Mexican descent completed surveys about sleep, acculturation, depressive symptoms and potential protective factor of social support. RESULTS: Acculturation, but not social support, significantly predicted increased sleep disruptions as well as overall feeling less refreshed upon waking across pregnancy. Moderation analysis indicated that more acculturated women who took longer to fall asleep reported increased depressive symptoms. Feeling refreshed upon waking also mediated the relationship between increased acculturation and elevated maternal depressive symptoms. CONCLUSIONS: Acculturation and altered sleep contribute to greater risk in Mexican-American women for maternal depressive symptoms in the perinatal period. These findings have implications for prevention and treatment of maternal mental health disorders, which may adversely affect perinatal outcomes in the vulnerable Mexican-American population.

Thought Disorder in Preschool Children with Attention Deficit/Hyperactivity Disorder (ADHD).

Preschool identification of and intervention for psychiatric symptoms has the potential for lifelong benefits. However, preschool identification of thought disorder, a symptom associated with long term risk for social and cognitive dysfunction, has received little attention with previous work limited to examining preschoolers with severe emotional and behavioral dysregulation. Using story-stem methodology, 12 children with ADHD and 12 children without ADHD, ages 4.0-6.0 years were evaluated for thought disorder. Thought disorder was reliably assessed (Cronbach's alpha = .958). Children with ADHD were significantly more likely than children without ADHD to exhibit thought disorder (75 vs 25 %; Fischer's Exact Test = .0391). Thought disorder can be reliably assessed in preschool children and is present in preschool children with psychiatric illness including preschool children with ADHD. Thought disorder may be identifiable in preschool years across a broad range of psychiatric illnesses and thus may be an appropriate target of intervention.

An Institutional Postdoctoral Research Training Program: Increasing Productivity of Postdoctoral Trainees.

OBJECTIVE: Postdoctoral training is a critical stage of career development, and there has been a national effort to increase the consistency and quality of postdoctoral experiences. However, much of the effort has gone towards improving the process of training with less effort focusing on the content of what should be achieved during postdoctoral training, primarily because of a lack of empirical evidence in this area. One possible predictor of later scientific productivity is the number of peer-reviewed papers published during postdoctoral training. This manuscript reports on efforts to increase postdoctoral productivity. METHOD: A single institution made postdoctoral training program changes designed to increase postdoctoral publication productivity. Postdoctoral publication productivity was compared between 114 trainees who matriculated prior to the changes and 20 trainees who matriculated after the changes. RESULTS: Postdoctoral trainees who matriculated after program changes had higher publication rates than postdoctoral trainees who matriculated prior to program changes [χ(2)(df = 15) = 31.4, p = .002]. Four or more postdoctoral publications are associated with the greatest likelihood of sustained posttraining publications; postdocs matriculating after the program changes were more than twice as likely to have four or more publications (55 vs 26%). CONCLUSIONS: Postdoctoral program changes designed to increase postdoctoral publication rates can be successful. Defining, for each postdoc, a minimal postdoctoral publication rate may be an appropriate component of individualized development plans.

Stability of P50 auditory sensory gating during sleep from infancy to 4 years of age.

The stability of cerebral inhibition was assessed across early childhood using a paired-click auditory sensory gating paradigm. The P50 ERP was measured during REM (or its infant analogue, active sleep) and NREM sleep in 14 children at approximately 3 months of age and again at approximately 4 years of age. Evoked response amplitudes, latencies, and the S2/S1 ratio of the amplitudes of the evoked responses were compared between the two visits. Significant reliability was found for the S2/S1 ratio (r = .73, p = .003) during REM but not non REM sleep (r = -.05, p = .88). A significant stimulus number by sleep stage interaction (F(1,12) = 17.1, p = .001) demonstrated that the response to the second stimulus decreased during REM but not NREM sleep. These findings suggest that this measure is stable during REM sleep across early childhood, is not affected by age, and is sleep-state dependent. P50 sensory gating is a biomarker which, if used properly, may provide a mechanism to further explore changes in the developing brain or may help with early screening for psychiatric illness vulnerability.

Neuropsychological functioning in childhood-onset psychosis and attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and childhood-onset psychosis (COP) are chronic, heterogeneous disorders with symptoms that frequently co-occur, but the etiology of their comorbidity is unknown. Studies of each disorder indicate that both ADHD and COP are associated with a range of neuropsychological weaknesses, but few neuropsychological studies have directly compared groups with ADHD and COP. METHODS: Groups with ADHD only (32 F, 48 M), COP only (5 F, 5 M), ADHD + COP (9 F, 21 M), and a control group with neither disorder (25 F, 44 M) completed a neuropsychological battery that included measures of verbal working memory, response inhibition, response speed and variability, and selective attention. RESULTS: All three clinical groups exhibited significantly lower performance versus the control group on all neuropsychological measures, whereas the only significant difference between the clinical groups was a significantly larger weakness in verbal working memory in the groups with COP. CONCLUSIONS: The frequent co-occurrence between COP and ADHD may reflect shared neuropsychological weaknesses that are most pronounced on measures of working memory and response variability.

Acculturation, maternal cortisol, and birth outcomes in women of Mexican descent.

OBJECTIVE: This study investigated the effects of acculturation on cortisol, a biological correlate of maternal psychological distress, and perinatal infant outcomes, specifically gestational age at birth and birth weight. METHODS: Fifty-five pregnant women of Mexican descent were recruited from a community hospital, and their saliva samples were collected at home for 3 days during pregnancy at 15 to 18 weeks (early), 26 to 32 weeks (mid), and more than 32 weeks (late) of gestation and once in the postpartum period (4-12 weeks). These values were used to determine the diurnal cortisol slope at each phase of pregnancy. Mothers also completed an acculturation survey and gave permission for a medical chart review to obtain neonate information. RESULTS: Multiple regression analyses determined that greater acculturation levels significantly predicted earlier infant gestational age at birth (R(2) = 0.09, p = .03). Results from t tests revealed that mothers of low-birth-weight infants (<2500 g) had significantly higher acculturation scores than mothers of infants with birth weight greater than 2500 g (t = -2.95, p = .005). A blunted maternal cortisol slope during pregnancy was also correlated with low birth weight (r = -0.29, p = .05) but not gestational age (r = -0.08, p = .59). In addition, more acculturated women had a flatter diurnal cortisol slope late in pregnancy (R(2) = 0.21, p = .01). Finally, diurnal maternal cortisol rhythms were identified as a potential mediator between increased acculturation and birth weight. CONCLUSIONS: This study associated increased acculturation with perinatal outcomes in the US Mexican population. This relationship may be mediated by prenatal maternal diurnal cortisol, which can program the health of the fetus leading to several adverse perinatal outcomes.

Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia.

The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.

Assessing disordered thoughts in preschoolers with dysregulated mood.

There is rising interest in identifying precursors to bipolar disorder symptoms, including thought disorder. Thought disorder is identified in adults through self-report and in school-aged children through parent report and child story-telling. This study is an exploration to determine if preschoolers with mood dysregulation have evidence of disordered thoughts using a story-stem completion method. Participants included two groups of 3.5-6 year-old children: 20 with mood dysregulation including manic symptoms and 11 typically developing comparison children. Children were administered story completion narratives including one story where the child character accidentally cuts him/herself while pretending to cook. The children were asked to complete the stories and their responses were analyzed for atypical themes consistent with disordered thoughts such as violence or bizarreness outside of the story or props coming to life. Thirty-five percentage of symptomatic preschoolers versus 0% of typically developing preschoolers ascribed independent actions to inanimate props (p = 0.03). Eighty percentage of symptomatic preschoolers versus 9% of typically developing preschoolers utilized props in a violent or bizarre manner outside the central story (p < 0.001). Preschool children with symptoms of dysregulated mood express themes related to the unusual use of story props which may indicate disordered thoughts. This preschool expression of dysregulated mood appears similar to and possibly continuous with school-age and adult versions of bipolar disorder.

Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia.

BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies. METHODS: Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia. RESULTS: The rs3087454 SNP, located at position -1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia. CONCLUSIONS: The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia.

An institutional postdoctoral research training program: predictors of publication rate and federal funding success of its graduates.

OBJECTIVE: The National Institute of Mental Health funds institutional National Research Service Awards (NRSA) to provide postdoctoral research training. While peer-reviewed publications are the most common outcome measure utilized, there has been little discussion of how publications should be counted or what factors impact the long-term publication rates of trainees in these programs. METHODS: The authors reviewed current curricula vitae from 92 graduates of an institutional NRSA and from the faculty mentors of that program to assess publications through 2005. Publications were weighted based on peer versus non-peer-reviewed and authorship position. Trainee and mentor factors were assessed for their impact on publication rates and on becoming principal investigators of larger scale federal grants such as a National Institutes of Health (NIH) R01. RESULTS: Weighted publication scores correlate with total publication rates at such a high rate that the two scores can be used interchangeably. Forty-three percent of graduates average at least one publication per year after completing the postdoctoral program; 20% were listed as an independent investigator on a larger federal grant. The number of publications published during postdoctoral training and additional funded training beyond that provided by the institutional NRSA are correlated with increased posttraining program publication rates; other factors including gender, terminal degree, number of publications prior to postdoctoral training, and mentor variables had no significant impact. Additional funded training, male gender, and increased time since completion of the training are associated with increased likelihood of larger grant federal funding. CONCLUSION: Weighting publications by whether they were peer-reviewed and by authorship position appears to have little benefit over a simple counting of the number of publications. Publication during research training and the pursuit of funding for additional individual research training may be appropriate short-term goals within an institutional research training program.

Effects of phosphatidylcholine and betaine supplements on women's serum choline.

Background: Maternal phosphatidylcholine supplements have shown benefit in the development of the human fetal brain, as assessed both by newborn physiological measurements and by a related decrease in later childhood behavioral abnormalities. However, the relatively low choline component of phosphatidylcholine mandates high doses that are difficult for pregnant women to consume. Objective: Betaine can substitute for some choline effects. The hypothesis was that betaine supplementation would significantly increase women's serum choline. Design: A three-arm crossover clinical trial was used to assess serum concentrations of choline after betaine supplements at two doses, in comparison with phosphatidylcholine supplementation. The effects of both a single dose and of one-week twice-daily doses were assessed in normal non-pregnant women. Results: Betaine supplements at two doses failed to increase serum choline concentrations after single administration or one-week twice-daily dosing. Phosphatidylcholine supplements raised choline concentrations after both single doses (mean change from baseline 8.34 ± 7.29 ng/ml, paired t = 3.24, df 7, p = 0.014, range 1-21 ng/ml, d' = 1.15) and one-week twice-daily doses (mean change from baseline 4.58 ± 3.68 ng/ml standard deviation; paired t = 3.51, df 7, p < 0.001, range 2-13 ng/ml, d' = 2.65). Betaine concentrations rose after both betaine and phosphatidylcholine supplementation. Conclusions: Betaine supplements did not substitute for phosphatidylcholine supplements, which raise serum choline concentrations both after a single dose and after repeated administration. However, serum betaine concentrations did rise after both betaine and phosphatidylcholine consumption and, therefore, betaine may be a stable indicator of choline intake.

Reliability of P50 auditory sensory gating measures in infants during active sleep.

This study assessed reliability of auditory sensory gating in young infants from 1-4 months of age using a paired-click paradigm in which auditory 'clicks' were presented at an interstimulus interval of 500 ms. Evoked potential component P1 was measured during periods of active sleep on two different occasions. Amplitudes, latencies, and ratio of the evoked potentials to each of the auditory clicks were compared. Significant reliability was found in the response ratio, response latency to the first stimulus, and response amplitude to the second stimulus, with a trend toward significance for response latency to the second stimulus and response amplitude to the first stimulus. The results suggest that auditory sensory gating can be reliably measured during active sleep in young infants and might be a useful tool in the study of neurodevelopmental disorders.

The stability of inhibitory and working memory deficits in children and adolescents who are children of parents with schizophrenia.

Cognitive deficits are a central feature of schizophrenia and occur in first-degree relatives of schizophrenic probands, even in the absence of psychotic symptoms. A number of cognitive domains have been implicated including measures of response inhibition and working memory. While the stability of cognitive deficits has been demonstrated in individuals with schizophrenia, stability of deficits has not been explored in first-degree relatives. This report focuses on 25 children (ages 6-15 years), all with at least one schizophrenic parent. The children were assessed twice, utilizing inhibitory and working memory tasks, with a mean 2.6 years between visits. Stop reaction time (a measure of motor inhibition) and performance on a counting span task (a measure of verbal working memory) were borderline to mildly impaired (compared with a typically developing comparison group) at both visits with similar effect sizes (stopping task time 1, effect size = 0.46, time 2 effect size = 0.50; counting span time 1 effect size = 0.53, time 2 effect size = 0.42). For these 2 tasks, individual age-adjusted scores also correlated across both time points (r = 0.41-0.76) suggesting that individual children maintained deficits across time. As etiologically driven strategies are developed for the cognitive deficits of schizophrenia, expansion of these treatments to relatives who share the cognitive but not the psychotic symptoms may be worth exploring.

Use of the ADOS and ADI-R in children with psychosis: importance of clinical judgment.

The Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview - Revised (ADI-R) are considered to be the 'gold standard' in diagnostic evaluations for autism. Developed as research tools and now gaining wide clinical use, the ADOS/ADI-R assessment package has been demonstrated to differentiate children with autism from those with other developmental disabilities; however, little work concerning the reliability and validity of the tools in children with a known history of psychosis has been undertaken. We report on the administration of the ADOS, ADI-R and clinical judgment in three cases of Childhood-Onset Schizophrenia. All 3 children met both ADOS and ADI-R criteria for an autism spectrum diagnosis, even though none of them received a clinical diagnosis of autism from either a research child psychiatrist or an experienced clinically trained, research psychologist with expertise in autism. Issues concerning overlap of symptom presentation and implications for research and clinical use of these assessment tools are discussed.

Regulation of a novel alphaN-catenin splice variant in schizophrenic smokers.

The alphaN-catenin (CTNNA2) gene represents a promising candidate gene for schizophrenia based upon previous genetic linkage, expression, and mouse knockout studies. CTNNA2 is differentially regulated by smoking in schizophrenic patients. In this report, the genomic structure of a primate-specific alphaN-catenin splice variant (alphaN-catenin III) is described. A comparison of alphaN-catenin III mRNA expression across postmortem hippocampi from schizophrenic and non-mentally ill smokers and non-smokers revealed a significant decrease in expression among patient non-smokers compared to all other groups. The recent evolutionary divergence of this gene, as well as the differences in gene expression in postmortem brain of schizophrenic non-smokers, supports the role of alphaN-catenin III as a novel disease susceptibility gene.

Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder.

OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.

Sleep Spindles and Auditory Sensory Gating: Two Measures of Cerebral Inhibition in Preschool-Aged Children are Strongly Correlated.

INTRODUCTION: Sleep spindles and P50 sensory gating are both reflective of cerebral inhibition, however, are differentially active during different phases of sleep. Assessing whether sleep spindles and P50 sensory gating correlate is a first step to evaluate whether these 2 forms of cerebral inhibition reflect overlapping neural circuits. METHODS: EEG data were collected between midnight and 6:00 AM on 13 healthy preschool-aged children. P50 sensory gating, calculated during REM sleep, negatively correlated with spindle duration (r=-.715, p=.006) and inter-peak density (r=.744, p=.004). There was a trend toward higher S2/S1 ratios being associated with fewer peaks per spindle (r=-.546, p=.053). In 4-year-olds, 2 established physiological measures of sensory gating and are correlated despite being maximally active during different stages of sleep. CONCLUSIONS: These results suggest there is an overlap in brain mechanisms underlying each gating mechanism.

Diminished Infant P50 Sensory Gating Predicts Increased 40-Month-Old Attention, Anxiety/Depression, and Externalizing Symptoms.

OBJECTIVE: When behavioral problems resulting from attentional difficulties present, often in preschool, it is unknown whether these problems represent preexisting altered brain development or new brain changes. This study examines whether infant sensory gating of auditory evoked potentials predicts parent-reported behavior at 40 months. METHOD: P50 sensory gating, an auditory evoked potential measure reflective of inhibitory processes in the brain, was measured in 50 infants around 70 days old. Parents, using the Child Behavior Checklist, reported on the child's behavior at 40 months. RESULTS: Controlling for gender, infants with diminished sensory gating had more problems later with externalizing behavior ( F = 4.17, ndf = 1, ddf = 46, p = .047), attentional problems ( F = 5.23, ndf = 1, ddf = 46, p = .027), and anxious/depressed symptoms ( F = 5.36, ndf = 1, ddf = 46, p = .025). CONCLUSION: Diminished infant P50 sensory gating predicts attention symptoms 3 years later. These results support the hypothesis that preschool attentional dysfunction may relate to altered brain development that is detectable years prior to symptom onset.