Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase.

β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase.

Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2.

Esophageal Bougienage for Management of Lodged Esophageal Coins: Safe, Effective, Efficient, and Underused.

Objectives: The aims of the study are to evaluate outcomes of esophageal bougienage for management of lodged esophageal coins and to assess the extent of bougienage usage and barriers among emergency providers.

Methods: We performed a retrospective chart review of pediatric patients with single lodged esophageal coins presenting to our single academic pediatric emergency department between November 2012 and December 2018. We compared procedural outcomes, complications, length of stay (LOS), and cost between those managed with bougienage and with endoscopy.

Pediatric Ovarian Torsion: Should You Go With the Flow?

Objectives: Ovarian torsion (OT) is an emergency that mandates early detection and surgical detorsion to avoid catastrophic consequences of further adnexal injury. Prompt ultrasound is critical for accurate diagnosis. Traditionally, evaluation of arterial and venous flow was used as a diagnostic tool for OT, but recent radiologic research has indicated that ovarian size and size discrepancy between sides is a better diagnostic criterion.

The Development and Pilot Testing of an Evidence-Based Cardiovascular Disease Risk-Prevention Program to Promote Healthy Lifestyle Behaviors Among African-American College Students - .

Objectives: Cardiovascular disease (CVD) is the leading cause of death in the United States. Among the risk factors for college students, obesity and physical inactivity are disproportionately high among African Americans (AAs), and while studies of the obesity epidemic have increased in recent years, few target AA college-aged students. This study developed and piloted an evidence-based, 15-week, 3-credit hour, CVD risk-prevention and intervention course, that used e-learning, web-based technologies, and a mobile application and compared its effects against a control course.

One Health Investigation of SARS-CoV-2 Infection and Seropositivity among Pets in Households with Confirmed Human COVID-19 Cases-Utah and Wisconsin, 2020.

Approximately 67% of U.S. households have pets.

Dazed and Confused: Altered Mental Status in an Adolescent Male.

Background: Absence status epilepticus (ASE) is a form of generalized nonconvulsive status epilepticus. ASE is characterized by impairment in consciousness, which can vary widely, making the diagnosis more difficult. The typical patient with ASE will be confused yet responsive and in a "trance-like state" with delayed speech, clumsy gait, and the ability to perform simple tasks after prompting.

ACEP SimBox: A Pediatric Simulation-Based Training Innovation.

Thirty million pediatric visits (<18 years old) occur across 5,000 US emergency departments (EDs) each year, with most of these cases presenting to community EDs. Simulation-based training is an effective method to improve and sustain EDs' readiness to triage and stabilize critically ill infants and children, but large simulation centers are mostly concentrated at academic hospitals. The use of pediatric simulation-based training has been limited in the community ED setting due to the high cost of equipment and limited access to content experts in pediatric critical care.

Point-of-Care Ultrasound Facilitates Management of Ruptured Ectopic Pregnancy.

Abdominal pain in the pregnant adolescent presents a diagnostic dilemma with potential life-threatening etiologies. We present a case where point-of-care ultrasound was used to facilitate diagnosis and expedite lifesaving management of a ruptured ectopic pregnancy. We further review the technique and literature for first-trimester transabdominal point-of-care ultrasound.

Sticking It Straight: Pediatric Procedure Curriculum Initiative.

Objectives: Literature demonstrates that pediatric residents are not graduating with procedural confidence and competency. This was confirmed with our own institution's Accreditation Council for Graduate Medical Education and internal surveys. Our primary objective was to improve procedural confidence among pediatric residents with the introduction of a mandatory longitudinal pediatric procedural curriculum, including simulation in combination with online modules.

Rams Have Heart, a Mobile App Tracking Activity and Fruit and Vegetable Consumption to Support the Cardiovascular Health of College Students: Development and Usability Study.

Background: With the increasing use of mobile devices to access the internet and as the main computing system of apps, there is a growing market for mobile health apps to provide self-care advice. Their effectiveness with regard to diet and fitness tracking, for example, needs to be examined. The majority of American adults fail to meet daily recommendations for healthy behavior.

Efficacy of a Psychosocial Pain Management Intervention for Men and Women With Substance Use Disorders and Chronic Pain: A Randomized Clinical Trial.

Importance: Chronic pain is common in those with substance use disorders (SUDs) and predicts poorer addiction treatment outcomes. A critical challenge for addiction treatment is to develop effective methods to improve pain-related and substance use-related outcomes for those in treatment for SUDs.

Objective: To examine the efficacy of an integrated behavioral pain management intervention (Improving Pain During Addiction Treatment [ImPAT]) for men and women with SUDs to treat pain, functioning, and substance use.

Cortical cellular diversity and development in schizophrenia.

While a definitive understanding of schizophrenia etiology is far from current reality, an increasing body of evidence implicates perturbations in early development that alter the trajectory of brain maturation in this disorder, leading to abnormal function in early childhood and adulthood. This atypical development likely arises from an interaction of many brain cell types that follow distinct developmental paths. Because both cellular identity and development are governed by the transcriptome and epigenome, two levels of gene regulation that have the potential to reflect both genetic and environmental influences, mapping "omic" changes over development in diverse cells is a fruitful avenue for schizophrenia research.

Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs.

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across 9 time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells. We identify widespread changes in the expression of both individual features and global patterns of transcription.

Characterizing the nuclear and cytoplasmic transcriptomes in developing and mature human cortex uncovers new insight into psychiatric disease gene regulation.

Transcriptome compartmentalization by the nuclear membrane provides both stochastic and functional buffering of transcript activity in the cytoplasm, and has recently been implicated in neurodegenerative disease processes. Although many mechanisms regulating transcript compartmentalization are also prevalent in brain development, the extent to which subcellular localization differs as the brain matures has yet to be addressed. To characterize the nuclear and cytoplasmic transcriptomes during brain development, we sequenced both RNA fractions from homogenate prenatal and adult human postmortem cortex using poly(A)+ and Ribo-Zero library preparation methods.

Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation.

Background: DNA methylation (DNAm) is a critical regulator of both development and cellular identity and shows unique patterns in neurons. To better characterize maturational changes in DNAm patterns in these cells, we profile the DNAm landscape at single-base resolution across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compare them to non-neurons (primarily glia) and prenatal homogenate cortex.

Results: We show that DNAm changes more dramatically during the first 5 years of postnatal life than during the entire remaining period.

A Citizen Science Approach to Determine Physical Activity Patterns and Demographics of Greenway Users in Winston-Salem, North Carolina.

Citizen science is a growing method of scientific discovery and community engagement. To date, there is a paucity of data using citizen scientists to monitor community level physical activity, such as bicycling or walking; these data are critical to inform community level intervention. Volunteers were recruited from the local community to make observations at five local greenways.

Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia.

The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition.

Convergent neural connectivity in motor impulsivity and high-fat food binge-like eating in male Sprague-Dawley rats.

Food intake is essential for survival, but maladaptive patterns of intake, possibly encoded by a preexisting vulnerability coupled with the influence of environmental variables, can modify the reward value of food. Impulsivity, a predisposition toward rapid unplanned reactions to stimuli, is one of the multifaceted determinants underlying the etiology of dysregulated eating and its evolving pathogenesis. The medial prefrontal cortex (mPFC) is a major neural director of reward-driven behavior and impulsivity.

Perceived Risk of Cardiovascular Disease and Health Behaviors in Black College Students.

For college students, the transition from adolescence to young adulthood can be a time of increased stress and negative health behaviors, such as poor diet and physical inactivity, that may lead to cardiovascular disease (CVD), the primary cause of death in the United States. Blacks are disproportionately prone to CVD. Perception of disease risk is a critical predictor of engagement in healthy lifestyle activities intended to reduce CVD development.