Exploring harmonic walking development in children with unilateral cerebral palsy and typically developing toddlers: Insights from walking experience.

This longitudinal study investigated the impact of the first independent steps on harmonic gait development in unilateral cerebral palsy (CP) and typically developing (TD) children. We analysed the gait ratio values (GR) by comparing the duration of stride/stance, stance/swing and swing/double support phases. Our investigation focused on identifying a potential trend towards the golden ratio value of 1.618, which has been observed in the locomotion of healthy adults as a characteristic of harmonic walking. Locomotor ability was assessed in both groups at different developmental stages: before and after the emergence of independent walking. Results revealed that an exponential fit was observed only after the first unsupported steps were taken. TD children achieved harmonic walking within a relatively short period (approximately one month) compared to children with CP, who took about seven months to develop harmonic walking. Converging values for stride/stance and stance/swing gait ratios, averaged on the two legs, closely approached the golden ratio in TD children (R2 = 0.9) with no difference in the analysis of the left vs right leg separately. In contrast, children with CP exhibited a trend for stride/stance and stance/swing (R2 = 0.7), with distinct trends observed for the most affected leg which did not reach the golden ratio value for the stride/stance ratio (GR = 1.5), while the least affected leg exceeded it (GR = 1.7). On the contrary, the opposite trend was observed for the stance/swing ratio. These findings indicate an overall harmonic walking in children with CP despite the presence of asymmetry between the two legs. These results underscore the crucial role of the first independent steps in the progressive development of harmonic gait over time.

The relationship between manual ability, dystonia and choreoathetosis severity and upper limb movement patterns during reaching and grasping in children and young adults with dyskinetic cerebral palsy.

INTRODUCTION: Impaired upper limb movements are a key feature in dyskinetic cerebral palsy (CP). However, information on how specific movement patterns relate to manual ability, performance and underlying movement disorders is lacking. Insight in these associations may contribute to targeted upper limb management in dyskinetic CP. This study aimed to explore associations between deviant upper limb movement patterns and (1) manual ability, (2) severity of dystonia/choreoathetosis, and (3) movement time/trajectory deviation during reaching and grasping. PARTICIPANTS/METHODS: Participants underwent three-dimensional upper limb analysis during reaching forwards (RF), reaching sideways (RS) and reach-and-grasp vertical (RGV) as well as clinical assessment. Canonical correlation and regression analysis with statistical parametric mapping were used to explore associations between clinical/performance parameters and movement patterns (mean and variability). RESULTS: Thirty individuals with dyskinetic CP participated (mean age 16±5 y; 20 girls). Lower manual ability was related to higher variability in wrist flexion/extension during RF and RS early in the reaching cycle (p < 0.05). Higher dystonia severity was associated with higher mean wrist flexion (40-82 % of the reaching cycle; p = 0.004) and higher variability in wrist flexion/extension (31-75 %; p < 0.001) and deviation (2-14 %; p = 0.007/60-73 %; p = 0.006) during RF. Choreoathetosis severity was associated with higher elbow pro/supination variability (12-19 %; p = 0.009) during RGV. Trajectory deviation was associated with wrist and elbow movement variability (p < 0.05). CONCLUSION: Current novel analysis of upper limb movement patterns and respective timings allows to detect joint angles and periods in the movement cycle wherein associations with clinical parameters occur. These associations are not present at each joint level, nor during the full movement cycle. This knowledge should be considered for individualized treatment strategies.

Altered upper limb kinematics in individuals with dyskinetic cerebral palsy in comparison with typically developing peers - A statistical parametric mapping study.

BACKGROUND: Dyskinetic cerebral palsy (DCP) is clinically characterized by involuntary movements and abnormal postures, which can aggravate with activity. While upper limb movement variability is often detected in the clinical picture, it remains unknown how movement patterns of individuals with DCP differ from typically developing (TD) peers. RESEARCH QUESTION: Do individuals with DCP show i) higher time-dependent standard deviations of upper limb joint angles and ii) altered upper limb kinematics in time and/or amplitude during functional upper limb tasks in comparison with TD individuals? METHODS: Three-dimensional upper limb movement patterns were cross-sectionally compared in 50 individuals with and without DCP during three functional tasks: reach forward (RF), reach and grasp vertical (RGV) and reach sideways (RS). Mean and point-wise standard deviations of angular waveform of the upper limb joint angles were compared between groups to evaluate differences in time and/or amplitude using traditional and non-linear registration statistical parametric mapping. RESULTS: Thirty-five extremities from 30 individuals (mean age 17y4m, range 5-25 y; MACS level I(n = 2); II(n = 15); III(n = 16); IV(n = 2)) with DCP and twenty TD individuals (mean age 16y8m, range 8-25 y) were evaluated. The DCP compared to TD group showed higher point-wise standard deviations at the level of all joints, which was time-dependent and varied between tasks. Mean wrist and elbow flexion was higher for the DCP group during RF (0-83 % wrist; 57-100 % elbow), RGV (0-82 % wrist; 12-100 % elbow) and RS (0-43 % wrist; 70-100 % elbow). SIGNIFICANCE: This is the first study exploring the movement patterns of individuals with DCP during reaching using quantitative measures. Analyzing these individual movement patterns by statistical parametric mapping (SPM) allows us to focus on both specific joint or on specific timing during the movement cycle. The individual information that this method yields can guide individual therapy aiming to improve reaching function in different parts of the movement cycle or evaluate intervention effects on upper extremity treatment.

Meta-Analysis of Mindfulness-Based Program Soles of the Feet for Disruptive Behaviors.

Mindfulness-based programs are a promising intervention modality for reducing disruptive behavior, and Soles of the Feet (SOF) is one program that teaches internal awareness of personal events (e.g., unpleasant emotions) and a self-regulation strategy to decrease disruptive behaviors. This study conducted a meta-analysis of single-case research design (SCRD) studies that implemented SOF to decrease disruptive behaviors. Existing SOF studies were evaluated using high-quality SCRD standards, resulting in 15 studies included in the analysis (49 participants; mean age 23.12 years (SD = 15.87); highly heterogeneous backgrounds). Studies were analyzed to calculate effect sizes using Tau-U, an innovative non-parametric statistical approach for estimating effect sizes in SCRD studies. The aggregated weighted Tau-U effect size of SOF across all studies was -0.87. Moderator analyses indicated SOF's effectiveness was robust across participant characteristics and delivery formats. This meta-analysis suggests that SOF is a moderately effective evidence-based practice for reducing disruptive behavior.

Revisiting the bipolar disorder with migraine phenotype: Clinical features and comorbidity.

INTRODUCTION: To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD). METHODS: In a cross-sectional study, we evaluated 721 adults with BD from the Mayo Clinic Bipolar Disorder Biobank and compared clinical correlates of those with and without a lifetime history of migraine. A structured clinical interview (DSM-IV) and a clinician-assessed questionnaire were utilized to establish a BD diagnosis, lifetime history of migraine, and clinical correlates. RESULTS: Two hundred and seven (29%) BD patients had a lifetime history of migraine. BD patients with migraine were younger and more likely to be female as compared to those without migraine (p values <0.01). In a multivariate logistic regression model, younger age (OR=0.98, p<0.01), female sex (OR=2.02, p<0.01), higher shape/weight concern (OR=1.04, p=0.02), greater anxiety disorder comorbidities (OR=1.24, p<0.01), and evening chronotype (OR=1.65, p=0.03) were associated with migraine. In separate regression models for each general medical comorbidity (controlled for age, sex, and site), migraines were significantly associated with fibromyalgia (OR=3.17, p<0.01), psoriasis (OR=2.65, p=0.03), and asthma (OR=2.0, p<0.01). Participants with migraine were receiving ADHD medication (OR=1.53, p=0.05) or compounds associated with weight loss (OR=1.53, p=0.02) at higher rates compared to those without migraine. LIMITATIONS: Study design precludes determination of causality. Migraine subtypes and features were not assessed. CONCLUSIONS: Migraine prevalence is high in BD and is associated with a more severe clinical burden that includes increased comorbidity with pain and inflammatory conditions. Further study of the BD-migraine phenotype may provide insight into common underlying neurobiological mechanisms.

Pediatric Prevention: Academic Behavior.

Many children in the United States are performing below basic standards in reading, mathematics, and writing. Children at risk for academic problems often have comorbid classroom behavior problems and/or are diagnosed with high-incidence disabilities. Early intervention to prevent academic problems is a key goal of school-wide response-to-intervention models. The goal of school-based instructional intervention is to increase children's strength of responding so basic academic skills can be combined to solve more complex tasks. Parents and caregivers can support intervention efforts at school by engaging in frequent communication with student assistance teams and helping children with academic work completion at home.

Effects of word overlap on generalized gains from a repeated readings intervention.

We compared children's gains in oral reading fluency after applying a standard fluency-building intervention to three training passages that differed in word overlap (high, low, and multiple exemplar) with an untrained generalization passage. Participants were 132 White and Hispanic third-grade children from two schools in the northeast and mountain west. Children were randomly assigned within classrooms to the three word overlap conditions, pre-tested on their assigned training and a common generalization passage, received a fluency-building intervention on their assigned training passage, and then post-tested on the same two passages. Regression analyses were conducted to examine the effects of word overlap condition on the children's fluency gains after controlling for pre-test fluency and classroom. Results revealed significantly larger priming and generalization effects for the multiple exemplar versus both the low- and high-word overlap conditions. Survival curves showed that a significantly larger proportion of children in the multiple exemplar condition survived as generalized responders at all generalization levels relative to the other two conditions. Implications for assessing and promoting generalized oral reading fluency in response-to-intervention models and directions for future research are discussed.

A mismatch repair-deficient and HPV-negative anorectal squamous cell carcinoma.

Invasive primary squamous cell carcinomas involving the anorectal region are challenging to manage. Microsatellite instability has been shown to impact clinical courses and outcomes of patients affected by many types of carcinomas. To the best of our knowledge, there are no reports on microsatellite instability in anorectal squamous cell carcinomas. Here, we report a HPV-negative anorectal squamous cell carcinoma which, despite cisplatin-based chemoradiation therapy, showed progression. Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response. This unique case illustrates that microsatellite instability testing and immunotherapy targeting immune checkpoint blockade should be considered for managing anorectal squamous cell carcinomas that fail conventional chemoradiation therapies or when patients are non-surgical candidates. This report provides the first evidence of microsatellite instability in anorectal squamous cell carcinomas and supports the role for microsatellite instability testing in this cancer type to optimize patient management.

Effect of continuous intrathecal baclofen therapy in children: a systematic review.

AIM: To investigate the effects of continuous intrathecal baclofen (ITB) therapy in children with cerebral palsy (CP) and other neurological conditions. METHOD: This systematic review was conducted using standardized methodology, searching four electronic databases (PubMed, Embase, CINAHL, Cochrane Library) for relevant literature published between inception and September 2017. Included studies involved continuous ITB as an intervention and outcome measures relating to all International Classification of Functioning, Disability and Health: Children and Youth (ICF-CY) components. RESULTS: Thirty-three studies were identified, of which one, including 17 children with spastic CP, produced level II evidence, and the others, mainly non-controlled cohort studies, level IV and V. Outcomes at body function level were most frequently reported. Results suggest continuous ITB may be effective in reducing spasticity and dystonia in CP, as well as other neurological conditions, and may improve the ease of care and quality of life of children with CP, but the level of evidence is low. INTERPRETATION: Despite three decades of applying ITB in children and a relatively large number of studies investigating the treatment effects, a direct link has not yet been demonstrated because of the low scientific quality of the primary studies. Further investigation into the effects of continuous ITB at all levels of the ICF-CY is warranted. Although large, controlled trials may be difficult to realize, national and international collaborations may provide opportunities. Also, multicentre prospective cohort studies with a long-term follow-up, employing harmonized outcome measures, can offer prospects to expand our knowledge of the effects of continuous ITB therapy in children. WHAT THIS PAPER ADDS: There is low-level evidence for continuous intrathecal baclofen (ITB) in children with cerebral palsy. Continuous ITB is effective in reducing spasticity and dystonia in non-controlled cohort studies. Evaluation of individual goals and systematic assessment of long-term effects in large cohort studies are required.

Agreement Between Structured Descriptive Assessments and Functional Analyses Conducted Over a Telehealth System.

This study examined whether experimental functional analyses (FAs) conducted by parents at home with coaching via telehealth would produce differentiated results, and compared these results to the functions identified from structured descriptive assessments (SDAs) also conducted by parents at home via telehealth. Four boys between the ages of 4- and 8-years old with intellectual and developmental disabilities and their parents participated. All assessments were conducted in the children's homes with their parents serving as intervention agents and with coaching from remote behavior therapists using videoconferencing technology. Parent-implemented FAs produced differentiated results for all 4 children in the study. Overall, analyzing antecedent-behavior (A-B) and behavior-consequence (B-C) relations from the SDA videos identified only half of the functions identified by the FAs. For children whose SDA results were differentiated, analyzing A-B relations correctly identified 4 of 5 functions. Analyzing B-C relations correctly identified 5 of 6 functions identified by the experimental FA, but overidentified attention for all children. Implications for conducting functional analyses and interpreting structured descriptive assessment via telehealth are discussed.

The Student Should Help the Teacher: a View From 30 Years as an ABA Trainer.

I characterize my efforts to train graduate students in applied behavior analysis as a shaping process that involves closely monitoring their performance, providing numerous opportunities to respond in a variety of contexts, gradually shifting the reinforcement criterion, differentially reinforcing improvement, and providing instruction and error correction when necessary. In line with the old adage that "the student should help the teacher", I also discuss how students are responsible in part for their own learning. To illustrate the importance of the student helping the teacher, I present a simple mathematical model that shows how two equally talented students can master skills at dramatically different rates by how frequently they respond to learning opportunities and apply what they learn.

Switch Rates During Acute Treatment for Bipolar II Depression With Lithium, Sertraline, or the Two Combined: A Randomized Double-Blind Comparison.

OBJECTIVE: The authors compared medication-induced mood switch risk (primary outcome), as well as treatment response and side effects (secondary outcomes) with three acute-phase treatments for bipolar II depression. METHOD: In a 16-week, double-blind, multisite comparison study, 142 participants with bipolar II depression were randomly assigned to receive lithium monotherapy (N=49), sertraline monotherapy (N=45), or combination treatment with lithium and sertraline (N=48). At each visit, mood was assessed using standardized rating scales. Rates of switch were compared, as were rates of treatment response and the presence and severity of treatment-emergent side effects. RESULTS: Twenty participants (14%) experienced a switch during the study period (hypomania, N=17; severe hypomania, N=3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N=89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response. CONCLUSIONS: Lithium monotherapy, sertraline monotherapy, and lithium/sertraline combination therapy were associated with similar switch and treatment response rates in participants with bipolar II depression. The dropout rate was higher in the lithium/sertraline combination treatment group, without any treatment acceleration advantage.

Children's preference for mixed- versus fixed-ratio schedules of reinforcement: A translational study of risky choice.

Laboratory research has shown that when subjects are given a choice between fixed-ratio and bi-valued mixed-ratio schedules of reinforcement, preference typically emerges for the mixed-ratio schedule even with a larger ratio requirement. The current study sought to replicate and extend these findings to children's math problem completion. Using an ABCBC reversal design, four fourth-grade students were given the choice of completing addition problems reinforced on either a fixed-ratio 5 schedule or one of three mixed-ratio schedules; an equivalent mixed-ratio (1, 9) schedule, a mixed-ratio (1, 11) schedule with a 20% larger ratio requirement, and an equally lean mixed-ratio (5, 7) schedule without the small fixed-ratio 1 component. This was followed by a reversal back to the preceding phase in which preference for the mixed-ratio schedule had been observed, and a final reversal back to the mixed-ratio (5, 7) phase. Findings were consistent with previous research in that all children preferred the mixed-ratio (1, 9) schedule over the equivalent fixed-ratio 5 schedule. Preference persisted for the leaner mixed-ratio (1, 11) schedule for three of the four children. Indifference or preference for the fixed-ratio 5 alternative was observed in phases containing the mixed-ratio (5, 7) schedule. These results extend previous research on risky choice to children's math problem completion and highlight the importance of a small ratio component in the emergence of preference for bi-valued mixed-ratio schedules. Implications of these results for arranging reinforcement to increase children's academic responding are discussed.

Choice in transition: Replication and extension to preschool children in a naturalistic setting.

This study replicated previous basic research into the dynamics of choice and extended this analysis to children's behavior in a naturalistic setting. Two preschoolers with disabilities were observed interacting with their teachers at baseline and during an experimental analysis involving four pairs of concurrent variable-interval schedules of adult attention implemented by an experimenter. Each child was exposed to four experimental phases in which the relative reinforcer rates for on- and off-task behavior were 10:1, 1:1, 1:10, and reversed back to 10:1. The 10:1 phase was designed to mimic the same schedules and types of adult attention observed at baseline. We used the generalized matching equation to model steady-state behavior at the end of the transition phases and to evaluate changes in sensitivity at various points throughout the phases. Choice in transition was evaluated by plotting log behavior ratios by session, cumulated time on- and off-task and cumulated attention for on- and off-task behavior by session, and interreinforcer behavior ratios following different sequences of the first four reinforcer deliveries. The generalized matching equation accounted for a large proportion of variance in steady-state responding, sensitivity values increased steadily throughout the phases, patterns of choice in transition were similar to those reported in basic research, and interreinforcer preference generally shifted toward the just-reinforced alternative. These findings are consistent with previous basic research and support the generality of the dynamics of choice to children's on- and off-task behavior reinforced by adult attention.

Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery.

The spread of Plasmodium falciparum multidrug resistance highlights the urgency to discover new targets and chemical scaffolds. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle. Chemogenomic profiling is an established tool for classification of drugs with similar mechanisms of action by comparing drug fitness profiles in a collection of mutants. Inferences of drug mechanisms of action and targets can be obtained by associations between shifts in drug fitness and specific genetic changes in the mutants. In this screen, P. falciparum, piggyBac single insertion mutants were profiled for altered responses to antimalarial drugs and metabolic inhibitors to create chemogenomic profiles. Drugs targeting the same pathway shared similar response profiles and multiple pairwise correlations of the chemogenomic profiles revealed novel insights into drugs' mechanisms of action. A mutant of the artemisinin resistance candidate gene - "K13-propeller" gene (PF3D7_1343700) exhibited increased susceptibility to artemisinin drugs and identified a cluster of 7 mutants based on similar enhanced responses to the drugs tested. Our approach of chemogenomic profiling reveals artemisinin functional activity, linked by the unexpected drug-gene relationships of these mutants, to signal transduction and cell cycle regulation pathways.

Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial.

This study evaluated the efficacy and tolerability of lisdexamfetamine (LDX) in the treatment of bipolar depression. Twenty-five outpatients with bipolar I or II disorder and syndromal depression despite at least 4 weeks of stable mood stabilizer and/or antipsychotic therapy were randomized to receive LDX (N=11) or placebo (N=14) in an 8-week, prospective, parallel-group, double-blind study. In the primary longitudinal analysis, LDX and placebo produced similar rates of improvement in depressive symptoms as assessed by the Montgomery-Asberg Depression Scale. However, LDX was associated with a statistically significantly greater rate of improvement in self-reported depressive symptoms and daytime sleepiness, and with greater reductions in fasting levels of low-density lipoprotein and total cholesterol. In the secondary baseline-to-endpoint analysis, LDX was associated with statistically significant improvements in self-reported measures of depression, daytime sleepiness, fatigue, and binge eating, as well as with improvements in fasting levels of triglycerides and low-density lipoprotein and total cholesterol. LDX was well tolerated and was not associated with any serious adverse events, but there was one case of suspected misuse. The small sample size (because of premature study termination by the funding sponsor) may have limited the detection of important drug-placebo differences. Larger studies on the use of psychostimulants for treatment of bipolar depression seem warranted.

Zonisamide in the treatment of bulimia nervosa: an open-label, pilot, prospective study.

OBJECTIVE: To assess preliminarily the effectiveness of zonisamide in bulimia nervosa. METHOD: This was an open-label, prospective, 12-week, flexible dose study of zonisamide in bulimia nervosa. The primary outcome was binge-purge episode frequency. RESULTS: Twelve individuals received zonisamide, 10 completed at least one post-baseline evaluation, and six completed the study. Mean dose at endpoint was 420 (SD = 215) mg/day. Zonisamide was associated with significant reductions in frequency of binge-purge episodes and binge-purge days as well as measures of binge eating behavior, purging behavior, clinical severity, obsessive-compulsive features, and depressive symptoms. Weight was unchanged. DISCUSSION: In this open-label trial, zonisamide was effective in bulimia nervosa, but associated with a high discontinuation rate.

A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain.

Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event.