Initiation Patterns and Transitions Among Adults Using Stimulant Drugs: Latent Transition Analysis.

BACKGROUND: The fourth wave of the drug overdose epidemic in the United States includes increasing rates of stimulant-involved overdose. Recent studies of transitions leading to stimulant misuse have shown complex patterns that are not universally applicable because they have isolated individual populations or individual behaviors. A comprehensive analysis of transitions between behaviors and the associations with present-day problematic drug use has not been conducted. OBJECTIVE: This study aims to determine whether adults from the general population who use stimulants initiate use through a heterogeneous combination of behaviors and quantify the association between these typologies with present-day problematic drug use. METHODS: Individuals who have reported use of any stimulant in their lifetime were recruited from the 2021 Survey of Nonmedical Use of Prescription Drugs Program, a nationally representative web-based survey on drug use, to participate in a rapid follow-up survey about their past stimulant use. Individuals were asked which stimulants they used, the reasons for use, the routes of administration, and the sources of the stimulant. For each stimulant-related behavior, they were asked at what age, between 6 and 30 years, they initiated each behavior in a 6-year time window. A latent transition analysis was used to characterize heterogeneity in initiation typologies. Mutually exclusive pathways of initiation were identified manually by the researchers. The association of these pathways with present-day problematic drug use was calculated using logistic regression adjusted by the current age of the respondent. RESULTS: From a total of 1329 participants, 740 (55.7%) reported lifetime prescription stimulant use and 1077 (81%) reported lifetime illicit stimulant use. Three typologies were identified. The first typology was characterized by illicit stimulant initiation to get high, usually via oral or snorting routes and acquisition from friends or family or a dealer (illicit experimentation). The second typology was characterized by low, but approximately equal probabilities of initiating 1-2 new behaviors in a time window, but no singular set of behaviors characterized the typology (conservative initiation). The third was characterized by a high probability of initiating many diverse combinations of behaviors (nondiscriminatory experimentation). The choice of drug initiated was not a strong differentiator. Categorization of pathways showed those who were only in an illicit experimentation status (reference) had the lowest odds of having severe present-day problematic drug use. Odds were higher for a conservative initiation-only status (odds ratio [OR] 1.84, 95% CI 1.14-2.94), which is higher still for those moving from illicit experimentation to conservative initiation (OR 3.50, 95% CI 2.13-5.74), and highest for a nondiscriminatory experimentation status (OR 5.45, 95% CI 3.39-8.77). CONCLUSIONS: Initiation of stimulant-related use behaviors occurred across many time windows, indicating that multiple intervention opportunities are presented. Screening should be continued throughout adulthood to address unhealthy drug use before developing into full substance use disorders.

Differing Behaviors Around Adult Nonmedical Use of Prescription Stimulants and Opioids: Latent Class Analysis.

BACKGROUND: The availability of central nervous system stimulants has risen in recent years, along with increased dispensing of stimulants for treatment of, for example, parent-reported attention-deficit/hyperactivity disorder in children and new diagnoses during adulthood. Typologies of drug use, as has been done with opioids, fail to include a sufficient range of behavioral factors to contextualize person-centric circumstances surrounding drug use. Understanding these patterns across drug classes would bring public health and regulatory practices toward precision public health. OBJECTIVE: The objective of this study was to quantitatively delineate the unique behavioral profiles of adults who currently nonmedically use stimulants and opioids using a latent class analysis and to contrast the differences in findings by class. We further evaluated whether the subgroups identified were associated with an increased Drug Abuse Screening Test-10 (DAST-10) score, which is an indicator of average problematic drug use. METHODS: This study used a national cross-sectional web-based survey, using 3 survey launches from 2019 to 2020 (before the COVID-19 pandemic). Data from adults who reported nonmedical use of prescription stimulants (n=2083) or prescription opioids (n=6127) in the last 12 months were analyzed. A weighted latent class analysis was used to identify the patterns of use. Drug types, motivations, and behaviors were factors in the model, which characterized unique classes of behavior. RESULTS: Five stimulant nonmedical use classes were identified: amphetamine self-medication, network-sourced stimulant for alertness, nonamphetamine performance use, recreational use, and nondiscriminatory behaviors. The drug used nonmedically, acquisition through a friend or family member, and use to get high were strong differentiators among the stimulant classes. The latter 4 classes had significantly higher DAST-10 scores than amphetamine self-medication (P<.001). In addition, 4 opioid nonmedical use classes were identified: moderate pain with low mental health burden, high pain with higher mental health burden, risky behaviors with diverse motivations, and nondiscriminatory behaviors. There was a progressive and significant increase in DAST-10 scores across classes (P<.001). The potency of the opioid, pain history, the routes of administration, and psychoactive effect behaviors were strong differentiators among the opioid classes. CONCLUSIONS: A more precise understanding of how behaviors tend to co-occur would improve efficacy and efficiency in developing interventions and supporting the overall health of those who use drugs, and it would improve communication with, and connection to, those at risk for severe drug outcomes.

Predicting Later Spelling from Kindergarten Spelling in U.S., Australian, and Swedish Children.

Purpose: Using data from 1,868 children from the US, Australia, and Sweden who took a 10-word spelling test in kindergarten and a standardized spelling test in Grades 1, 2, and (except for the Australian children) Grade 4, we examined two questions. First, does the quality of a child's errors on the kindergarten test help predict later spelling performance even after controlling for the number of correct responses on the kindergarten test? Second, does spelling develop at a faster pace in Swedish than in English? Method: We measured kindergarten error quality based on the number of letter additions, deletions, and substitutions needed to transform each error into the correct spelling. Using mixed-model analyses, we examined the relationship of this and other variables to later spelling performance. Results: Kindergarten error quality contributed significantly to the prediction of later spelling performance even after consideration of the number of correct spellings in kindergarten and other relevant variables. The Swedish children showed more rapid growth in spelling than the U.S. and Australian children, a difference that may reflect the greater transparency of spelling-to-sound links in Swedish. Conclusion: Information from a spelling test that is typically discarded-information about the nature of the errors-has value.

Disasters and corruption: public expectations and tolerance-evidence from Mexico.

Disaster corruption is a vexing problem, damaging state legitimacy and exacerbating human suffering. Mexico has a history of both major disasters and persistently high levels of corruption. A magnitude 7.1 earthquake in 2017 provided an opportunity to study change over time in expectations and tolerance of corruption in disaster relief. Twenty years earlier, Mexico City residents expected, on average, essentially three out of 10 hypothetical trucks loaded with humanitarian assistance to be lost to corruption but expressed near zero tolerance of such conduct. By 2018-19, Mexico City residents expected more than one-half of all relief, six out of 10 trucks, to be stolen, and could tolerate three out of 10 trucks being pilfered. Similar results were found at the national level. Hence, Mexicans appear to be giving up on the state. Addressing corruption in disaster risk reduction and humanitarian relief specifically might provide a template for improving public trust across other state institutions.

Addressing genetic essentialism: Sharpening context in behavior genetics.

Evidence of a causal role for genes in human behavior underpins genetic essentialism, the scientifically flawed and socially hazardous idea that heritable characteristics are immutable. Behavior geneticists can challenge this idea by designing research that brings the contextual dependence of heritability estimates into sharper focus, and by incorporating a relevant statement into research reports and public outreach.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

In Search of Cognitive Promotive and Protective Factors for Word Reading.

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success.

Exploring the Influence of Early Childhood Education and Care on the Etiology of Achievement.

The present study used a genetically-sensitive quantile regression approach to examine the relation between participation in early childhood education and care (ECEC) and subsequent school performance in literacy and numeracy at grades 3, 5, 7, and 9. The sample consisted of 1255 twin pairs (596 MZ; 659 DZ) with information on both ECEC and the National Assessment Program-Literacy and Numeracy (NAPLAN) scores from the Twin Study of NAPLAN. Results indicated variation in heritability estimates across the distributions of achievement, suggesting that different patterns of etiological influences may exist among children of different ability levels. Additionally, the results provided no evidence that ECEC significantly influenced achievement, and in the genetically-sensitive analyses, no evidence that ECEC moderated the influences of heritability of achievement for typically advantaged children. These results suggest that ECEC may not provide the levels of environmental support for later achievement that advocates claim, although we acknowledge that ECEC quality, which was not measured in the current study, may make a difference in whether or not ECEC influences achievement.

An amide-based sulfenamide prodrug of gamma secretase inhibitor BMS-708163 delivers parent drug from an oral conventional solid dosage form in male beagle dog.

The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2-7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.

Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite.

In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.

Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African-American youth.

BACKGROUND: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. OBJECTIVE: To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. METHODS: We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African-American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. RESULTS: Genome-wide significant effects were observed at rs1555839 (p=4.03×10-8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. CONCLUSION: This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene-brain-behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

The Academic Development Study of Australian Twins (ADSAT): Research Aims and Design.

The Academic Development Study of Australian Twins was established in 2012 with the purpose of investigating the relative influence of genes and environments in literacy and numeracy capabilities across two primary and two secondary school grades in Australia. It is the first longitudinal twin project of its kind in Australia and comprises a sample of 2762 twin pairs, 40 triplet sets and 1485 nontwin siblings. Measures include standardized literacy and numeracy test data collected at Grades 3, 5, 7 and 9 as part of the National Assessment Program: Literacy and Numeracy. A range of demographic and behavioral data was also collected, some at multiple longitudinal time points. This article outlines the background and rationale for the study and provides an overview for the research design, sample and measures collected. Findings emerging from the project and future directions are discussed.

Differential Influences of Genes and Environment Across the Distribution of Reading Ability.

We partitioned early childhood reading into genetic and environmental sources of variance and examined the full distribution of ability levels from low through normal to high as computed by quantile regression. The full sample comprised twin pairs measured at preschool (n = 977), kindergarten (n = 1028), grade 1 (n = 999), and grade 2 (n = 1000). Quantile regression analyses of the full distribution of literacy ability showed genetic influence in all grades from preschool to grade 2. At preschool, the low end of the distribution had higher genetic influence than the high end of the distribution and the shared environment influence was the opposite. These shared environment influences of preschool became insignificant with formal schooling. This suggests that higher scores in pre-literacy skills (preschool) are more influenced by shared environment factors, though these are short-lived. This study discusses the factors that may be influencing the results.

Little Evidence That Socioeconomic Status Modifies Heritability of Literacy and Numeracy in Australia.

Socioeconomic status (SES) has been found to moderate the influence of genes and the environment on cognitive ability, such that genetic influence is greater when SES is higher, and the shared environment is greater when SES is lower, but not in all Western countries. The effects of both family and school SES on the heritability of literacy and numeracy in Australian twins aged 8, 10, 12, and 14 years with 1,307, 1,235, 1,076, and 930 pairs at each age, respectively, were tested. Shared environmental influences on Grade 3 literacy were greater with low family SES, and no other moderating effects of SES were significant. These findings are contrasted with results from the United States and the United Kingdom.

Cross-Country Differences in Parental Reporting of Symptoms of ADHD.

Previous studies within the United States suggest there are cultural and contextual influences on how Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms are perceived. If such influences operate within a single country, they are likely to also occur between countries. In the current study, we tested whether country differences in mean ADHD scores also reflect cultural and contextual differences, as opposed to actual etiological differences. The sample for the present study included 974 participants from four countries tested at two-time points, the end of preschool and the end of 2nd grade. Consistent with previous research, we found lower mean ADHD scores in Norway and Sweden in comparison to Australia and the United States, and we tested four explanations for these country differences: 1) Genuine etiological differences, 2) Slower introduction to formal academic skills in Norway and Sweden than in the United States and Australia that indicated a context difference, 3) Under-reporting tendency in Norway and Sweden, or 4) Over-reporting tendency in the United States and Australia. Either under-or over-reporting would be examples of cultural differences in the perception of ADHD symptoms. Of these explanations, results of ADHD measurement equivalence tests across countries rejected the first three explanations and supported the fourth explanation: an over-reporting tendency in the United States and Australia. These findings indicate that parental reporting of ADHD symptoms is more accurate in Norway and Sweden than in Australia and the United States, and thus have important clinical and educational implications for how parental reporting informs an ADHD diagnosis in these countries.

Understanding Comorbidity Between Specific Learning Disabilities.

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies.

Differential impact of trait sluggish cognitive tempo and ADHD inattention in early childhood on adolescent functioning.

BACKGROUND: Sluggish cognitive tempo (SCT) is distinct from attention-deficit/hyperactivity disorder inattention (ADHD-IN) and concurrently associated with a range of impairment domains. However, few longitudinal studies have examined SCT as a longitudinal predictor of adjustment. Studies to date have all used a relatively short longitudinal time span (6 months to 2 years) and only rating scale measures of adjustment. Using a prospective, multi-method design, this study examined whether SCT and ADHD-IN were differentially associated with functioning over a 10-year period between preschool and the end of ninth grade. METHODS: Latent state-trait modeling determined the trait variance (i.e. consistency across occasions) of SCT and ADHD-IN across four measurement points (preschool and the end of kindergarten, first grade, and second grade) in a large population-based longitudinal sample (N = 976). Regression analyses were used to examine trait SCT and ADHD-IN factors in early childhood as predictors of functioning at the end of ninth grade (i.e. parent ratings of psychopathology and social/academic functioning, reading and mathematics academic achievement scores, processing speed and working memory). RESULTS: Both SCT and ADHD-IN contained more trait variance (Ms = 65% and 61%, respectively) than occasion-specific variance (Ms = 35% and 39%) in early childhood, with trait variance increasing as children progressed from preschool through early elementary school. In regression analyses: (a) SCT significantly predicted greater withdrawal and anxiety/depression whereas ADHD-IN did not uniquely predict these internalizing domains; (b) ADHD-IN uniquely predicted more externalizing behaviors whereas SCT uniquely predicted fewer externalizing behaviors; (c) SCT uniquely predicted shyness whereas both SCT and ADHD-IN uniquely predicted global social difficulties; and (d) ADHD-IN uniquely predicted poorer math achievement and slower processing speed whereas SCT more consistently predicted poorer reading achievement. CONCLUSIONS: Findings of this study - from the longest prospective sample to date - provide the clearest evidence yet that SCT and ADHD-IN often differ when it comes to the functional outcomes they predict.

Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors.

Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.

Literacy acquisition influences children's rapid automatized naming.

Previous research has established that learning to read improves children's performance on reading-related phonological tasks, including phoneme awareness (PA) and nonword repetition. Few studies have investigated whether literacy acquisition also promotes children's rapid automatized naming (RAN). We tested the hypothesis that literacy acquisition should influence RAN in an international, longitudinal population sample of twins. Cross-lagged path models evaluated the relationships among literacy, PA, and RAN across four time points from pre-kindergarten through grade 4. Consistent with previous research, literacy showed bidirectional relationships with reading-related oral language skills. We found novel evidence for an effect of earlier literacy on later RAN, which was most evident in children at early phases of literacy development. In contrast, the influence of earlier RAN on later literacy was predominant among older children. These findings imply that the association between these two related skills is moderated by development. Implications for models of reading development and for dyslexia research are discussed.

Glenohumeral osteoarthritis: frequency of underlying diagnoses and the role of arm dominance-a retrospective analysis in a community-based musculoskeletal practice.

Patients with shoulder pain are commonly seen in adult primary care, and are typically referred to musculoskeletal specialists when their symptoms are persistent. Rotator cuff disorders (RCD) most commonly underlie non-traumatic shoulder pain in adults, and glenohumeral osteoarthritis (GHOA) has been considered to be relatively uncommon (Nakagawa et al., J Shoulder Elb Surg 8:580-584, 1999). Our impression has been that GHOA affects significant numbers of patients, is less well studied, and may be under recognized. Among adults referred to a musculoskeletal practice for shoulder pain evaluation, we determined the relative numbers of patients with a clinical diagnosis of RCD and GHOA by age and by gender, assessed the role of handedness in GHOA, and the proportion of patients with underlying conditions (versus primary or idiopathic GHOA). We also assessed the frequency of progression to operative management over a defined time interval. This is a retrospective case series of patients presenting to a musculoskeletal referral practice for shoulder pain. Patients with a clinical diagnosis of GHOA were identified with electronic medical records, and then assessed for demographic data, physical measures, comorbidities, and progression to surgical intervention within 2 years. Among non-traumatic shoulder pain patients presenting to our practice during a 9-month period in 2013, RCD was diagnosed in 984 patients, and GHOA was diagnosed in 209 patients. 152 of the GHOA patients (73%) had primary (idiopathic) GHOA, without associated inflammatory conditions or cuff arthropathy. Primary GHOA affected the dominant arm in 38.7%, the non-dominant arm in 33.8%, and was bilateral in 27.5%. Patients diagnosed with primary GHOA were older than those with RCD (69.8 ± 12.2 vs 57.1 ± 15.1; p = 0.0001). Women represented 54% of cases of primary GHOA, and their presentation age was older than men (72.9 ± 11.2 vs 66.1 ± 12.4; p = 0.0005). Primary GHOA patients had a mean BMI of 31.0 ± 6.3, 48.7% had hyperlipidemia and 57.2% had hypertension. 24.3% were treated surgically within 2 years of follow-up. GHOA is a significant cause of shoulder pain in older age groups, and the majority of these patients have primary (idiopathic) GHOA. Primary GHOA affects dominant and non-dominant arms at similar rates, suggesting that anatomical and/or systemic factors are more important than overuse in GHOA pathogenesis. Given the prominence of GHOA in older age groups, changes in population demographics, and limitations of non-operative treatment, continued increases in shoulder replacement surgery are likely. Efforts to further understand GHOA pathogenesis and develop new, more effective therapies are advocated.