Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model.R01 DA011716 - NIDA NIH HHS; DA011716 - NIDA NIH HH

Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar- Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d- Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model

Expression profile of CREB knockdown in myeloid leukemia cells.

BackgroundThe cAMP Response Element Binding Protein, CREB, is a transcription factor that regulates cell proliferation, differentiation, and survival in several model systems, including neuronal and hematopoietic cells. We demonstrated that CREB is overexpressed in acute myeloid and leukemia cells compared to normal hematopoietic stem cells. CREB knockdown inhibits leukemic cell proliferation in vitro and in vivo, but does not affect long-term hematopoietic reconstitution.MethodsTo understand downstream pathways regulating CREB, we performed expression profiling with RNA from the K562 myeloid leukemia cell line transduced with CREB shRNA.ResultsBy combining our expression data from CREB knockdown cells with prior ChIP data on CREB binding we were able to identify a list of putative CREB regulated genes. We performed extensive analyses on the top genes in this list as high confidence CREB targets. We found that this list is enriched for genes involved in cancer, and unexpectedly, highly enriched for histone genes. Furthermore, histone genes regulated by CREB were more likely to be specifically expressed in hematopoietic lineages. Decreased expression of specific histone genes was validated in K562, TF-1, and primary AML cells transduced with CREB shRNA.ConclusionWe have identified a high confidence list of CREB targets in K562 cells. These genes allow us to begin to understand the mechanisms by which CREB contributes to acute leukemia. We speculate that regulation of histone genes may play an important role by possibly altering the regulation of DNA replication during the cell cycle

Music Educators' Uses of the Kodály-Approach in U.S. Elementary School Music Learning Environments.

In this study, I examined how and why Kodály-trained music educators used pure and blended forms of Kodály-Approach instruction in their music class learning environments. I sent a nationwide music educator survey (N = 536, 14.89%) to the Organization of American Kodály Educators membership (OAKE). Responses to survey item 9 (n = 499) indicated that more than half of respondents blended Kodály-Approach instruction with other forms of instruction, but mostly used Kodály-Approach instruction in their United States music class learning environments (n = 332, 66.53%). I conducted 3 case studies to understand participants’ in-depth experiences when using Kodály-Approach instruction in their classrooms. Qualitative themes and sub-themes emerged related to how and why the educators used Kodály-Approach instruction in pure and blended forms. A synthesis of 3 overarching ideas formed from the above-mentioned qualitative themes and sub-themes. Analysis of repertoire selection and use also revealed themes and sub-themes. Content analysis of lesson plan data confirmed that lesson plan data corroborated with teacher-observation data and teacher interview data, and that lesson plan data corroborated with participants’ survey responses. Participant-perceived and researcher-perceived limitations to Kodály-Approach instruction were discovered through analysis of teacher observations, interviews, and open-ended questionnaire responses. Additional discussion points revealed how music educators in the United States are choosing to use specific forms of training and ways of teaching in relation to Kodály-Approach instruction. Suggestions for training centers of Kodály-Approach instruction and recommendations for future research were highlighted in the discussion section of this study

In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial

ObjectiveTo determine whether performing comprehensive chromosome screening (CCS) and transferring a single euploid blastocyst can result in an ongoing pregnancy rate that is equivalent to transferring two untested blastocysts while reducing the risk of multiple gestation.DesignRandomized, noninferiority trial.SettingAcademic center for reproductive medicine.Patient(s)Infertile couples (n = 205) with a female partner less than 43 years old having a serum anti-Müllerian hormone level ≥1.2 ng/mL and day 3 FSH <12 IU/L.Intervention(s)Randomization occurred when at least two blastocysts were suitable for trophectoderm biopsy. The study group (n = 89) had all viable blastocysts biopsied for real-time, polymerase chain reaction–based CCS and single euploid blastocyst transfer. The control group (n = 86) had their two best-quality, untested blastocysts transferred.Main Outcome Measure(s)The ongoing pregnancy rate to ≥24 weeks (primary outcome) and the multiple gestation rate.Result(s)The ongoing pregnancy rate per randomized patient after the first ET was similar between groups (60.7% after single euploid blastocyst transfer vs. 65.1% after untested two-blastocyst transfer; relative risk [RR], 0.9; 95% confidence interval [CI], 0.7–1.2). A difference of greater than 20% in favor of two-blastocyst transfer was excluded. The risk of multiple gestation was reduced after single euploid blastocyst transfer (53.4% to 0%), and patients were nearly twice as likely to have an ongoing singleton pregnancy (60.7% vs. 33.7%; RR, 1.8; 95% CI, 1.3–2.5).Conclusion(s)In women ≤42 years old, transferring a single euploid blastocyst results in ongoing pregnancy rates that are the same as transferring two untested blastocysts while dramatically reducing the risk of twins.Clinical Trial Registration NumberNCT01408433

Implementing measurable goals for diversity, equity, and inclusion in Clinical and Translational Science Awards leadership

Charting a benchmarking strategy is recommended to measure improvements in equal leadership opportunities for minorities and women in the Clinical Translational Science Awards Consortium (CTSAs). Academic institutions that support diversity, equity, and inclusion (DEI) initiatives should demonstrate a willingness to track their progress with established metrics. In the fall of 2020, the CTSAs convened a virtual conference, which started a dialogue on developing measurable objectives to ensure accountability for DEI goals. Using qualitative and quantitative data from breakout sessions, the authors analyze participant responses to the following recommendation, “develop a common metric and dashboard with regular reporting on diversity in CTSA leadership, with an emphasis on increasing female and Black Indigenous, People Of Color (BIPOC) representation to 30% each,” to understand the impact and challenges associated with implementing metrics within CTSAs. Thematic analysis revealed that white supremacist culture and demographic composition are obstacles to establishing metrics. Participants expressed uncertainty about the perception of token roles. Additionally, participants believed that DEI targets can increase diversity in perspectives and approaches to translational science. Implications for CTSAs include establishing CTSA-wide benchmarks for DEI initiatives, which includes a baseline of the existing DEI climate to assess institutional norms and measurable objectives to track progress

Extending the Functionality of Behavioural Change-Point Analysis with k-Means Clustering: A Case Study with the Little Penguin (Eudyptula minor)

We present a simple framework for classifying mutually exclusive behavioural states within the geospatial lifelines of animals. This method involves use of three sequentially applied statistical procedures: (1) behavioural change point analysis to partition movement trajectories into discrete bouts of same-state behaviours, based on abrupt changes in the spatiotemporal autocorrelation structure of movement parameters; (2) hierarchical multivariate cluster analysis to determine the number of different behavioural states; and (3) k-means clustering to classify inferred bouts of same-state location observations into behavioural modes. We demonstrate application of the method by analysing synthetic trajectories of known ‘artificial behaviours’ comprised of different correlated random walks, as well as real foraging trajectories of little penguins (Eudyptula minor) obtained by global-positioning-system telemetry. Our results show that the modelling procedure correctly classified 92.5% of all individual location observations in the synthetic trajectories, demonstrating reasonable ability to successfully discriminate behavioural modes. Most individual little penguins were found to exhibit three unique behavioural states (resting, commuting/active searching, arearestricted foraging), with variation in the timing and locations of observations apparently related to ambient light, bathymetry, and proximity to coastlines and river mouths. Addition of k-means clustering extends the utility of behavioural change point analysis, by providing a simple means through which the behaviours inferred for the location observations comprising individual movement trajectories can be objectively classified

Improving the equity landscape at U.S. academic institutions: 10 strategies to lead change

In the United States, disparities with respect to race, ethnicity, and gender are common across academic institutions, particularly those that are large and have health research-oriented missions. Disparity-affected issues include leadership roles, funding, tenure, and salary. This paper presents a review of the current literature describing those disparities, with a focus on health professions serving major universities in the United States, and proposes approaches to create greater diversity, equity, inclusion and belonging (DEIB) within them. While many organizations nationally are working to address DEIB disparities, academic institutions can benefit from implementing structured approaches and training to nurture their cultures, foster DEIB, and promote psychological safety. We present a literature-based 10-component approach institutions can adopt with relative ease and thus positively support advancing their DEIB engagement. These 10 strategies include the following: Clearly stating DEI values; Conducting gap analyses to identify issues; Using incentives to propel change; Removing bias from recruiting processes; Implementing blind applications processes; Diversifying selection committees; Creating inter-institutional partnerships that truly represent shared power; Developing people and the pipeline; Formalizing mentorship and sponsorship programs; and instituting anti-bias training. Easily implementable strategies can both foster change and build the will and confidence to pursue larger DEIB goals in the future

Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder.

Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 ± 2.5 years; range 7-15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 ± 2.5 years; range 7-15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p \u3c 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = -0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = -0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self-injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self-injury