Modeling the development of cognitive reserve in children: A residual index approach.

OBJECTIVE: To model cognitive reserve (CR) longitudinally in a neurodiverse pediatric sample using a residual index approach, and to test the criterion and construct validity of this index. METHOD: Participants were N = 115 children aged 9.5-13 years at baseline (MAge = 10.48 years, SDAge = 0.61), and n = 43 (37.4%) met criteria for ADHD. The CR index represented variance in Matrix Reasoning scores from the WASI that was unexplained by MRI-based brain variables (bilateral hippocampal volumes, total gray matter volumes, and total white matter hypointensity volumes) or demographics (age and sex). RESULTS: At baseline, the CR index predicted math computation ability (estimate = 0.50, SE = 0.07, p < .001), and word reading ability (estimate = 0.26, SE = 0.10, p = .012). Longitudinally, change in CR over time was not associated with change in math computation ability (estimate = -0.02, SE = 0.03, p < .513), but did predict change in word reading ability (estimate = 0.10, SE = 0.03, p < .001). Change in CR was also found to moderate the relationship between change in word reading ability and white matter hypointensity volume (estimate = 0.10, SE = 0.05, p = .045). CONCLUSIONS: Evidence for the criterion validity of this CR index is encouraging, but somewhat mixed, while construct validity was evidenced through interaction between CR, brain, and word reading ability. Future research would benefit from optimization of the CR index through careful selection of brain variables for a pediatric sample.

In-person versus online delivery of a behavioral sleep intervention (Sleeping Sound©) for children with ADHD: protocol for a parallel-group, non-inferiority, randomized controlled trial.

BACKGROUND: Children with Attention-Deficit/Hyperactivity Disorder (ADHD) often experience sleep difficulties such as difficulty initiating and maintaining sleep. Problem sleep may impact children's daily functioning and behaviors and exacerbate ADHD symptoms. Most effective behavioral interventions to improve sleep are conducted in person, limiting accessibility to treatment for individuals in remote or rural communities or those who are unable to attend a clinic. This trial aims to assess the efficacy of delivering an established behavioral intervention online, Sleeping Sound with ADHD©, compared to a face-to-face delivery mode. METHODS: This parallel group, non-inferiority, randomized controlled trial (RCT) will include at least 68 children, aged 5-12 years old with ADHD. Families of children will be recruited from private developmental and psychological clinics and social media, within the state of Western Australia (WA). Once written informed consent and baseline questionnaires are completed, families are randomized to receive the behavioral intervention either in-person or online via Telehealth services. The intervention targets the assessment and management of reported sleep problems, through two individual consultations and a follow-up phone call with a trained clinician. The sleep outcomes assessed consist of a parent-reported sleep questionnaire and actigraphy. DISCUSSION: To the best of our knowledge, this is the first RCT to investigate sleep treatment modality for children with ADHD. If effective, clinicians can provide an evidence-based sleep intervention in an accessible manner. TRIAL REGISTRATION: ANZCTR, ACTRN12621001681842 . Registered 9 December 2021-Retrospectively registered.

Assessing non-right-handedness and atypical cerebral lateralisation as predictors of paediatric mental health difficulties.

Research utilising handedness as a proxy for atypical language lateralisation has invoked the latter to explain increased mental health difficulties in left-/mixed-handed children. The current study investigated unique associations between handedness and language lateralisation, handedness and mental health, and language lateralisation and mental health, in children, to elucidate the role of cerebral lateralisation in paediatric mental health. Participants were N = 64 (34 females [52%]; MAge = 8.56 years; SDAge = 1.33; aged 6-12 years) typically developing children. Hand preference was assessed via a reaching task, language lateralisation was assessed using functional transcranial Doppler ultrasonography (fTCD) during an expressive language task, and mental health was assessed with the Strengths and Difficulties Questionnaire. As hypothesised, leftward hand preference predicted increased general mental health issues in children, with a strong relationship noted between leftward hand preference and the emotional symptoms subscale. Contrary to expectation, no relationship was found between direction of language lateralisation and general mental health issues, although exploratory analyses of subscales showed rightward lateralisation to predict conduct problems. Hand preference and direction of language lateralisation were also not significantly associated. The relatively weak relationship between manual and language laterality coupled with discrepancy regarding the predictive scope of each phenotype (i.e., hand preference predicts overall mental health, whereas language laterality predicts only conduct problems) suggests independent developmental pathways for these phenotypes. The role of manual laterality in paediatric mental health warrants further investigation utilising a neuroimaging method with higher spatial resolution.

Behavioral Sleep Interventions for Children With ADHD: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate intervention characteristics and components within behavioral sleep interventions in school-aged children with ADHD and examine evidence related to effectiveness. METHOD: A systematic review was conducted using PsycINFO, Embase, MEDLINE, PubMed, and OpenGray. The subsequent meta-analysis used sleep outcomes to produce comparable effect sizes (Hedges' g) and compare intervention effects between randomized controlled trials and pre-post studies. RESULTS: Eleven articles satisfied the inclusion criteria (562 children, across all groups, aged 5-14 years, M = 8.71). Studies reported improvements in sleep although there was marked heterogeneity between studies and limited use of objective sleep measures within them. On average, intervention groups improved more than control groups in the five randomized controlled trials (-0.46, 95% CI = [-0.58, -0.35], k = 4). CONCLUSION: The findings support the use of behavioral sleep interventions for school-aged children with ADHD. Findings suggest that brief, individualized intervention may be more effective than standardized.

IQ predictors in pediatric opsoclonus myoclonus syndrome: a large international cohort study.

AIM: To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD: In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS: Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION: Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.

'Scared to death' dyspnoea from the hospitalised patient's perspective.

Because dyspnoea is seldom experienced by healthy people, it can be hard for clinicians and researchers to comprehend the patient's experience. We collected patients' descriptions of dyspnoea in their own words during a parent study in which 156 hospitalised patients completed a quantitative multidimensional dyspnoea questionnaire. These volunteered comments describe the severity and wide range of experiences associated with dyspnoea and its impacts on a patients' life. They provide insights not conveyed by structured rating scales. We organised these comments into the most prominent themes, which included sensory experiences, emotional responses, self-blame and precipitating events. Patients often mentioned air hunger ('Not being able to get air is the worst thing that could ever happen to you.'), anxiety, and fear ('Scared. I thought the world was going to end, like in a box.'). Their value in patient care is suggested by one subject's comment: 'They should have doctors experience these symptoms, especially dyspnoea, so they understand what patients are going through.' Patients' own words can help to bridge this gap of understanding.

Controlled Delivery of 80 mg Aerosol Furosemide Does Not Achieve Consistent Dyspnea Relief in Patients.

PURPOSE: Aerosol furosemide may be an option to treat refractory dyspnea, though doses, methods of delivery, and outcomes have been variable. We hypothesized that controlled delivery of high dose aerosol furosemide would reduce variability of dyspnea relief in patients with underlying pulmonary disease. METHODS: Seventeen patients with chronic exertional dyspnea were recruited. Patients rated recently recalled breathing discomfort on a numerical rating scale (NRS) and the multidimensional dyspnea profile (MDP). They then performed graded exercise using an arm-ergometer. The NRS was completed following each exercise grade, and the MDP was repeated after a pre-defined dyspnea threshold was reached. During separate visits, patients received either aerosol saline or 80 mg of aerosol furosemide in a randomized, double-blind, crossover design. After treatment, graded exercise to the pre-treatment level was repeated, followed by completion of the NRS and MDP. Treatment effect was defined as the difference between pre- and post-treatment NRS at end exercise, expressed in absolute terms as % Full Scale. "Responders" were defined as those showing treatment effect ≥ 20% of full scale. RESULTS: Final analysis included 15 patients. Neither treatment produced a statistically significant change in NRS and there was no significant difference between treatments (p = 0.45). There were four "responders" and one patient whose dyspnea worsened with furosemide; two patients were responders with saline, of whom one also responded to furosemide. No adverse events were reported. CONCLUSIONS: High dose controlled delivery aerosol furosemide was not statistically different from saline placebo at reducing exercise-induced dyspnea. However, a clinically meaningful improvement was noted in some patients.

A Multidimensional Profile of Dyspnea in Hospitalized Patients.

BACKGROUND: Dyspnea is prevalent among hospitalized patients but little is known about the experience of dyspnea among inpatients. We sought to characterize the multiple sensations and associated emotions of dyspnea in patients admitted with dyspnea to a tertiary care hospital. METHODS: We selected patients who reported breathing discomfort of at least 4/10 on admission (10 = unbearable). Research staff recruited 156 patients within 24 hours of admission and evaluated daily patients' current and worst dyspnea with the Multidimensional Dyspnea Profile; patients participated in the study 2.6 days on average. The Multidimensional Dyspnea Profile assesses overall breathing discomfort (A1), intensity of five sensory qualities of dyspnea, and 5 negative emotional responses to dyspnea. Patients were also asked to rate whether current levels of dyspnea were "acceptable." RESULTS: At the time of the first research interview, patients reported slight to moderate dyspnea (A1 median 4); however, most patients reported experiencing severe dyspnea in the 24 hours before the interview (A1 mean 7.8). A total of 54% of patients with dyspnea ≥4 on day 1 found the symptom unacceptable. The worst dyspnea each day in the prior 24 hours usually occurred at rest. Dyspnea declined but persisted through hospitalization for most patients. "Air hunger" was the dominant sensation, especially when dyspnea was strong (>4). Anxiety and frustration were the dominant emotions associated with dyspnea. CONCLUSIONS: This first multidimensional portrait of dyspnea in a general inpatient population characterizes the sensations and emotions dyspneic patients endure. The finding that air hunger is the dominant sensation of severe dyspnea has implications for design of laboratory models of these sensations and may have implications for targets of palliation of symptoms.

Presence of Spotters Improves Bench Press Performance: A Deception Study.

Sheridan, A, Marchant, DC, Williams, EL, Jones, HS, Hewitt, PA, and Sparks, SA. Presence of spotters improves bench press performance: a deception study. J Strength Cond Res 33(7): 1755-1761, 2019-Resistance exercise is a widely used method of physical training in both recreational exercise and athletic populations. The use of training partners and spotters during resistance exercise is widespread, but little is known about the effect of the presence of these individuals on exercise performance. The purpose of the current study was to investigate the effect of spotter presence on bench press performance. Twelve recreationally trained participants (age, 21.3 ± 0.8 years, height, 1.82 ± 0.1 m, and mass, 84.8 ± 11.1 kg) performed 2 trials of 3 sets to failure at 60% of 1 repetition maximum on separate occasions. The 2 trials consisted of spotters being explicitly present or hidden from view (deception). During the trials, total repetitions (reps), total weight lifted, ratings of perceived exertion (RPE), and self-efficacy were measured. Total reps and weight lifted were significantly greater with spotters (difference = 4.5 reps, t = 5.68, p < 0.001 and difference = 209.6 kg, t = 5.65, p < 0.001, respectively). Although RPE and local RPE were significantly elevated in the deception trials (difference = 0.78, f = 6.16, p = 0.030 and difference = 0.81, f = 5.89, p = 0.034, respectively), self-efficacy was significantly reduced (difference = 1.58, f = 26.90, p < 0.001). This study demonstrates that resistance exercise is improved by the presence of spotters, which is facilitated by reduced RPE and increased self-efficacy. This has important implications for athletes and clients, who should perform resistance exercise in the proximity of others, to maximize total work performed.

Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration.

We generated a knockout mouse for the neuronal-specific ß-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3-/- mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining ß-tubulin isotypes results in equivalent total ß-tubulin levels in Tubb3-/- and wild-type mice. Despite similar levels of total ß-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other ß-tubulins.

Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform.

BACKGROUND: The detection of somatic mutations in primary tumors is critical for the understanding of cancer evolution and targeting therapy. Multiple technologies have been developed to enable the detection of such mutations. Next generation sequencing (NGS) is a new platform that is gradually becoming the technology of choice for genotyping cancer samples, owing to its ability to simultaneously interrogate many genomic loci at massively high efficiency and increasingly lower cost. However, multiple barriers still exist for its broader adoption in clinical research practice, such as fragmented workflow and complex bioinformatics analysis and interpretation. METHODS: We performed validation of the QIAGEN GeneReader NGS System using the QIAact Actionable Insights Tumor Panel, focusing on clinically meaningful mutations by using DNA extracted from formalin-fixed paraffin-embedded (FFPE) colorectal tissue with known KRAS mutations. The performance of the GeneReader was evaluated and compared to data generated from alternative technologies (PCR and pyrosequencing) as well as an alternative NGS platform. The results were further confirmed with Sanger sequencing. RESULTS: The data generated from the GeneReader achieved 100% concordance with reference technologies. Furthermore, the GeneReader workflow provides a truly integrated workflow, eliminating artifacts resulting from routine sample preparation; and providing up-to-date interpretation of test results. CONCLUSION: The GeneReader NGS system offers an effective and efficient method to identify somatic (KRAS) cancer mutations.

A longitudinal study of child sleep in high and low risk families: relationship to early maternal settling strategies and child psychological functioning.

OBJECTIVES: To investigate whether sleep disturbances previously found to characterise high risk infants: (a) persist into childhood; (b) are influenced by early maternal settling strategies and (c) predict cognitive and emotional/behavioural functioning. METHODS: Mothers experiencing high and low levels of psychosocial adversity (risk) were recruited antenatally and longitudinally assessed with their children. Mothers completed measures of settling strategies and infant sleep postnatally, and at 12 and 18 months, infant age. At five years, child sleep characteristics were measured via an actigraphy and maternal report; IQ and child adjustment were also assessed. RESULTS: Sleep disturbances observed in high-risk infants persisted at five years. Maternal involvement in infant settling was greater in high risk mothers, and predicted less optimal sleep at five years. Poorer five year sleep was associated with concurrent child anxiety/depression and aggression, but there was limited evidence for an influence of early sleep problems. Associations between infant/child sleep characteristics and IQ were also limited. CONCLUSIONS: Early maternal over-involvement in infant settling is associated with less optimal sleep in children, which in turn, is related to child adjustment. The findings highlight the importance of supporting parents in the early development of good settling practices, particularly in high-risk populations.

Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding.

We describe the genome sequencing of an anonymous individual of African origin using a novel ligation-based sequencing assay that enables a unique form of error correction that improves the raw accuracy of the aligned reads to >99.9%, allowing us to accurately call SNPs with as few as two reads per allele. We collected several billion mate-paired reads yielding approximately 18x haploid coverage of aligned sequence and close to 300x clone coverage. Over 98% of the reference genome is covered with at least one uniquely placed read, and 99.65% is spanned by at least one uniquely placed mate-paired clone. We identify over 3.8 million SNPs, 19% of which are novel. Mate-paired data are used to physically resolve haplotype phases of nearly two-thirds of the genotypes obtained and produce phased segments of up to 215 kb. We detect 226,529 intra-read indels, 5590 indels between mate-paired reads, 91 inversions, and four gene fusions. We use a novel approach for detecting indels between mate-paired reads that are smaller than the standard deviation of the insert size of the library and discover deletions in common with those detected with our intra-read approach. Dozens of mutations previously described in OMIM and hundreds of nonsynonymous single-nucleotide and structural variants in genes previously implicated in disease are identified in this individual. There is more genetic variation in the human genome still to be uncovered, and we provide guidance for future surveys in populations and cancer biopsies.