Relationship between skill training and skill transfer through the example of bimanual motor learning.

Skill training aims to improve the performance of the task at hand and aims to transfer the acquired skill to related tasks. Both skill training and skill transfer are part of our everyday lives, and essential for survival, and their importance is reflected in years of research. Despite these enormous efforts, however, the complex relationship between skill training and skill transfer is not yet portrayed completely. Building upon two theories, we probed this relationship through the example of bimanual learning with a large cross-sectional design (N = 450) using an online framework. We designed five training tasks which differed in the variance of the training material (schema theory) and three transfer tasks differing in their similarity to the training task (identical elements theory). Theoretically, the five training tasks and the three transfer tasks varied approximately linearly from each other. Empirical data, however, suggested merely the presence of three statistically different training tasks and two significantly different transfer tasks, indicating a nonlinear relationship. Against our expectation, Bayesian statistics suggested that the type of skill training was not related to the type of skill transfer. However, the amount of skill training was positively related to the amount of skill transfer. Together, we showed that motor learning studies can be conducted online. Further, our results shed light on the complex relationship between skill training and skill transfer. Understanding this relationship has wide-ranging practical implications for the general population, particularly for musicians, athletes and patients recovering from injury.

VU6036720: The First Potent and Selective In Vitro Inhibitor of Heteromeric Kir4.1/5.1 Inward Rectifier Potassium Channels.

Heteromeric Kir4.1/Kir5.1 (KCNJ10/KCNJ16) inward rectifier potassium (Kir) channels play key roles in the brain and kidney, but pharmacological tools for probing their physiology and therapeutic potential have not been developed. Here, we report the discovery, in a high-throughput screening of 80,475 compounds, of the moderately potent and selective inhibitor VU0493690, which we selected for characterization and chemical optimization. VU0493690 concentration-dependently inhibits Kir4.1/5.1 with an IC50 of 0.96 µM and exhibits at least 10-fold selectivity over Kir4.1 and ten other Kir channels. Multidimensional chemical optimization of VU0493690 led to the development of VU6036720, the most potent (IC50 = 0.24 µM) and selective (>40-fold over Kir4.1) Kir4.1/5.1 inhibitor reported to date. Cell-attached patch single-channel recordings revealed that VU6036720 inhibits Kir4.1/5.1 activity through a reduction of channel open-state probability and single-channel current amplitude. Elevating extracellular potassium ion by 20 mM shifted the IC50 6.8-fold, suggesting that VU6036720 is a pore blocker that binds in the ion-conduction pathway. Mutation of the "rectification controller" asparagine 161 to glutamate (N161E), which is equivalent to small-molecule binding sites in other Kir channels, led to a strong reduction of inhibition by VU6036720. Renal clearance studies in mice failed to show a diuretic response that would be consistent with inhibition of Kir4.1/5.1 in the renal tubule. Drug metabolism and pharmacokinetics profiling revealed that high VU6036720 clearance and plasma protein binding may prevent target engagement in vivo. In conclusion, VU6036720 represents the current state-of-the-art Kir4.1/5.1 inhibitor that should be useful for probing the functions of Kir4.1/5.1 in vitro and ex vivo. SIGNIFICANCE STATEMENT: Heteromeric inward rectifier potassium (Kir) channels comprising Kir4.1 and Kir5.1 subunits play important roles in renal and neural physiology and may represent inhibitory drug targets for hypertension and edema. Herein, we employ high-throughput compound library screening, patch clamp electrophysiology, and medicinal chemistry to develop and characterize the first potent and specific in vitro inhibitor of Kir4.1/5.1, VU6036720, which provides proof-of-concept that drug-like inhibitors of this channel may be developed.

Closing the gap: Understanding African American asthma knowledge and beliefs.

BACKGROUND: African American children are disproportionately affected by asthma (13% vs 8% non-Hispanic white Americans) and experience 30% higher asthma-related deaths than whites. Knowledge regarding asthma and asthma treatment among African Americans has been postulated as a potential contributor to this observed health disparity. Compared with the amount of studies on asthma, few investigations provide insight into the baseline knowledge and beliefs of African Americans regarding asthma. OBJECTIVE: Assess knowledge and beliefs regarding asthma symptoms, diagnosis, treatment, prognosis, and stigmas in a general community sample of African Americans. METHODS: Using community-based participatory research techniques, we developed and implemented a cross-sectional survey to explore asthma knowledge and beliefs among African American adults in a Midwestern city. RESULTS: Among the 158 African American adults who completed the survey, general asthma knowledge was good, with awareness of the genetic contribution to asthma and general asthma symptomatology (eg, 92% aware of nighttime cough as a symptom). However, asthma-related misconceptions were also revealed. Thirty-three percent of respondents were concerned about addiction to asthma medication, and 60% of respondents believed that inhaled corticosteroids were dangerous or did not know. CONCLUSION: This study reveals important insights into asthma knowledge and beliefs among African Americans that may be used to address disparities in asthma outcomes in this population.

Validity of the 3-Minute All-Out Exercise Test on the CompuTrainer.

The 3-minute all-out exercise test (3MT) has emerged as a useful procedure for identifying critical power (CP) and the finite work capacity above CP (W') within a single visit. The CP concept enables for the prediction of exhaustive time limits (T(LIMs)) for a wide range of severe intensity power outputs and is a method for prescribing high-intensity interval training (HIIT). Road cyclists often use the CompuTrainer for indoor HIIT. The purpose of this study was to validate the 3MT for use on the CompuTrainer. On 4 separate visits, 10 competitive cyclists performed a 3MT, and three separate constant-load bouts projected to yield exhaustive T(LIMs) of 3, 6, and 9 minutes, respectively, using the Computrainer. Actual CP and W' were calculated using the linear work-time (W-t) and power-inverse time (1/t) models. The results for CP (W) from the 3MT (215 ± 40), the W-t model (212 ± 36), and the 1/t model (213 ± 36) did not differ (F = 2.96, p = 0.11, η2(p) = 0.43). Similarly, the results for W' (kJ) for the 3MT (11.2 ± 4.0), the W-t model (12.1 ± 6.5), and the 1/s model (11.7 ± 6.3) did not differ (F = 2.40, p = 0.15, η2(p) = 0.375). We conclude that use of the 3MT and the CP concept for performance assessment and HIIT prescription on the CompuTrainer is a valid procedure.

Pediatric systemic juvenile idiopathic arthritis-related lung disease: Description of clinical cohort and review of management.

CONTEXT: Since the early 2010s, there has been an increased awareness of interstitial lung disease in systemic juvenile idiopathic arthritis (sJIA-LD) in pediatric patients. Despite the increase in prevalence of sJIA-LD, little is known about this disease process and effective therapeutic management. OBJECTIVES: To identify and characterize the disease process and management of interstitial lung disease related to systemic juvenile idiopathic arthritis. STUDY DESIGN: In this single-center, retrospective case series of 9 patients, we analyze demographic, clinical, radiographic, and laboratory data to corroborate common clinical characteristics and describe an approach for diagnosis and monitoring of sJIA-LD. DATA EXTRACTION: All data was extracted through electronic medical records and individually reviewed by two pediatric pulmonologists and two pediatric rheumatologists. RESULTS: Our results were similar to other described cases of sJIA-LD as patients in our cohort were more likely to be younger, have a history of macrophage activation syndrome and prior use of biologic therapies. In contrast to prior studies, they did not present with peripheral lymphadenopathy and hepatosplenomegaly. LIMITATIONS: The cohort size was small and data is reflective of one center's approach to management of a rare lung disease process. CONCLUSION: Interstitial lung disease due to sJIA is rare and management can be difficult in these complex patients.More research is necessary to understand the increased incidence and treatment of sJIA-LD in pediatric population.

Chronic Cough: Characterizing and Quantifying Burden in Adults Using a Nationwide Electronic Health Records Database.

Chronic cough is a common condition; until recently, no International Classification of Diseases (ICD) code for chronic cough existed; therefore, the true scope and burden of chronic cough is unclear. Using established algorithms, we examined chronic cough patients and their risk profiles, recurrent cough episodes, and subsequent 1-year health care utilization in the nationwide Cerner EHR data resource, compared with those with acute cough. An ICD-based algorithm was applied to the Cerner Health Facts EHR database to derive a phenotype of chronic cough defined as three ICD-based "cough" encounters 14-days apart over a 56-to-120-day period from 2015 to 2017. Demographics, comorbidities, and outcomes (1-year outpatient, emergency, and inpatient encounters) were collected for the chronic cough cohort and acute cough cohort. The chronic cough cohort was 61.5% female, 70.4% white, and 15.2% African American, with 13.7% being of Asian, Native American, or unknown race. Compared with the acute cough cohort, chronic cough patients were more likely to be older, female, and have chronic pulmonary disease, obesity, and depression. Predictors of recurrent chronic cough were older age and race. Those with chronic cough had more outpatient (2.48 ± 2.10 vs. 1.48 ± 0.99; SMD = 0.94), emergency (1.90 ± 2.26 vs. 1.23 ± 0.68; SMD = 0.82), and inpatient (1.11 ± 0.36 vs. 1.05 ± 0.24, SMD = 0.24) encounters compared with acute cough. While EHR-based data may provide a useful resource to identify chronic cough phenotypes, supplementary data approaches and screening methods for chronic cough can further identify the scope of the problem.

Chemical Catalysis Guides Structural Identification for the Major In Vivo Metabolite of the BET Inhibitor JQ1.

The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor in vivo pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the (+)-JQ1 primary metabolite using chemical catalysis methods. Treatment of (+)-JQ1 with tetrabutylammonium decatungstate under photochemical conditions resulted in selective formation of an aldehyde at the 2-position of the thiophene ring [(+)-JQ1-CHO], which was further reduced to the 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative LC/MS analysis of (+)-JQ1-OH to the product obtained from liver microsomes suggested (+)-JQ1-OH as the major metabolite of (+)-JQ1. The 2-thienyl position was then substituted to generate a trideuterated (-CD3, (+)-JQ1-D) analog having half-lives that were 1.8- and 2.8-fold longer in mouse and human liver microsomes, respectively. This result unambiguously confirmed (+)-JQ1-OH as the major metabolite of (+)-JQ1. These studies demonstrate an efficient process for studying drug metabolism and identifying the metabolic soft spots of bioactive compounds.

Vitamin D Oral Replacement in Children With Obesity Related Asthma: VDORA1 Randomized Clinical Trial.

Children with asthma and obesity are more likely to have lower vitamin D levels, but the optimal replacement dose is unknown in this population. The objective of this study is identifying a vitamin D dose in children with obesity-related asthma that safely achieves serum vitamin D levels of ≥ 40 ng/mL. This prospective multisite randomized controlled trial recruited children/adolescents with asthma and body mass index ≥ 85% for age/sex. Part 1 (dose finding), evaluated 4 oral vitamin D regimens for 16 weeks to identify a replacement dose that achieved serum vitamin D levels ≥ 40 ng/mL. Part 2 compared the replacement dose calculated from part 1 (50,000 IU loading dose with 8,000 IU daily) to standard of care (SOC) for 16 weeks to identify the proportion of children achieving target serum 25(OH)D level. Part 1 included 48 randomized participants. Part 2 included 64 participants. In Part 1, no SOC participants achieved target serum level, but 50-72.7% of participants in cohorts A-C achieved the target serum level. In part 2, 78.6% of replacement dose participants achieved target serum level compared with none in the SOC arm. No related serious adverse events were reported. This trial confirmed a 50,000 IU loading dose plus 8,000 IU daily oral vitamin D as safe and effective in increasing serum 25(OH)D levels in children/adolescents with overweight/obesity to levels ≥ 40 ng/mL. Given the critical role of vitamin D in many conditions complicating childhood obesity, these data close a critical gap in our understanding of vitamin D dosing in children.

Mammalian facial muscles contain muscle spindles.

Muscle spindles are sensory receptors in skeletal muscle that provide information on muscle length and velocity of contraction. Previous studies noted that facial muscles lack muscle spindles, but recent reports indicate that the human platysma muscle and "buccal" muscles contain spindles. Mammalian facial muscles are active in social communication, vibrissa movement, and vocalizations, including human speech. Given these functions, we hypothesized that facial muscles contain muscle spindles, and we predicted that humans would have the greatest number, given the role our lips play in speech. We examined previously sectioned and stained (with H&E and trichrome stains) orbicularis oris (upper fibers) and zygomaticus (major) muscles across a broad phylogenetic range of mammalian species, spanning a wide distribution of body size and ecological niche, to assess the presence of muscle spindles. We also stained several sections with Sirius red to highlight the muscle spindle capsule. Our results indicate that mammalian facial muscles contain muscle spindles, supporting our hypothesis. Contrary to our prediction, though, humans (and other primates) had the lowest number of muscle spindles. We instead found that the carnivoran sample and the horse sample had the greatest number of spindles. Larger body size and nocturnality were also associated with a greater number of spindles. These results must be viewed with caution, though, as our sample size was small and there are critical mammalian taxa missing. Future work should use an expanded phylogenetic range of mammalian species to ascertain the role that phylogeny plays in muscle spindle presence and count.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Communication in clinical research: Uncertainty, stress, and emotional labor.

This exploratory study investigated perceptions of competent vs. contentious communication in the workplace as experienced by Clinical Research Professionals (CRPs) managing or coordinating clinical research. Qualitative data collected from a 90-min focus group interview were thematically analyzed using open and axial coding and constant comparison. Findings suggest CRPs associate contentious communication with uncertainty, stress, and emotional labor. Further, although many participants regularly utilize effective conflict and emotion management strategies, they lack confidence in both knowledge and efficacy of competent communication, stress management, and emotion management skills. Conclusions support revising "Wheel of Competencies" figure representing the Joint Task Force for Clinical Trial Competency framework. Study limitations and suggestions for future research and educational training are discussed.

Obesity-related asthma in children: A role for vitamin D.

Excess adipose tissue predisposes to an enhanced inflammatory state and can contribute to the pathogenesis and severity of asthma. Vitamin D has anti-inflammatory properties and low-serum levels are seen in children with asthma and in children with obesity. Here we review the intersection of asthma, obesity, and hypovitaminosis D in children. Supplementation with vitamin D has been proposed as a simple, safe, and inexpensive adjunctive therapy in a number of disease states. However, little research has examined the pharmacokinetics of vitamin D and its therapeutic potential in children who suffer from obesity-related asthma.

Synthesis of the Siderophore Coelichelin and Its Utility as a Probe in the Study of Bacterial Metal Sensing and Response.

A convergent total synthesis of the siderophore coelichelin is described. The synthetic route also provided access to acetyl coelichelin and other congeners of the parent siderophore. The synthetic products were evaluated for their ability to bind ferric iron and promote growth of a siderophore-deficient strain of the Gram-negative bacterium Pseudomonas aeruginosa under iron restriction conditions. The results of these studies indicate coelichelin and several derivatives serve as ferric iron delivery vehicles for P. aeruginosa.

Behavioral Hyperventilation and Central Sleep Apnea in Two Children.

Behavioral hyperventilation is a rarely recognized cause of central sleep apnea (CSA) among children. We report two pediatric patients who presented with prolonged central sleep apnea secondary to behavioral hyperventilation. One patient also had a prolonged corrected QT (QT(C)) interval resulting from hyperventilation

Identifying and explicating variation among friends with benefits relationships.

This two-study report identifies and validates a typology containing seven types of "friends with benefits relationships" (FWBRs). Study 1 asked heterosexual students to define the term FWBR and to describe their experience with the relationship type. Qualitative analysis of these data identified seven types of FWBRs (true friends, network opportunism, just sex, three types of transition in [successful, failed, and unintentional], and transition out). Study 2 quantitatively differentiates these relationship types in the amount of nonsexual interaction, strength of the friendship at the first sexual interaction, and history of romantic relationships with the FWBR partner (before the FWBR, after it, or both). Results from both studies clearly suggest that FWBRs represent a diverse set of relationship formulations where both the benefits (i.e., repeated sexual contact) and the friends (i.e., relationship between partners) vary widely. In many cases, FWBRs represent a desire for, or an attempt at, shifting the relationship from friends to a romantic partnership. Other implications are discussed, as are limitations and directions for future research. The diverse nature of FWBRs provides challenges for researchers that likely require multiple methods and theoretical frames.

EPOXI at comet Hartley 2.

Understanding how comets work--what drives their activity--is crucial to the use of comets in studying the early solar system. EPOXI (Extrasolar Planet Observation and Deep Impact Extended Investigation) flew past comet 103P/Hartley 2, one with an unusually small but very active nucleus, taking both images and spectra. Unlike large, relatively inactive nuclei, this nucleus is outgassing primarily because of CO(2), which drags chunks of ice out of the nucleus. It also shows substantial differences in the relative abundance of volatiles from various parts of the nucleus.