Are the average gait speeds during the 10 meter and 6 minute walk tests redundant in Parkinson disease?

Published in final edited form as: Gait Posture. 2017 February ; 52: 178–182. doi:10.1016/j.gaitpost.2016.11.033.We investigated the relationships between average gait speed collected with the 10Meter Walk Test (Comfortable and Fast) and 6Minute Walk Test (6MWT) in 346 people with Parkinson disease (PD) and how the relationships change with increasing disease severity. Pearson correlation and linear regression analyses determined relationships between 10Meter Walk Test and 6MWT gait speed values for the entire sample and for sub-samples stratified by Hoehn & Yahr (H&Y) stage I (n=53), II (n=141), III (n=135) and IV (n=17). We hypothesized that redundant tests would be highly and significantly correlated (i.e. r>0.70, p<0.05) and would have a linear regression model slope of 1 and intercept of 0. For the entire sample, 6MWT gait speed was significantly (p<0.001) related to the Comfortable 10 Meter Walk Test (r=0.75) and Fast 10Meter Walk Test (r=0.79) gait speed, with 56% and 62% of the variance in 6MWT gait speed explained, respectively. The regression model of 6MWT gait speed predicted by Comfortable 10 Meter Walk gait speed produced slope and intercept values near 1 and 0, respectively, especially for participants in H&Y stages II-IV. In contrast, slope and intercept values were further from 1 and 0, respectively, for the Fast 10Meter Walk Test. Comfortable 10 Meter Walk Test and 6MWT gait speeds appeared to be redundant in people with moderate to severe PD, suggesting the Comfortable 10 Meter Walk Test can be used to estimate 6MWT distance in this population.This study was funded by the Davis Phinney Foundation, the Parkinson's Disease Foundation, and the National Institutes of Health (R01 NS077959, K12 HD055931, UL1 TR000448). The funding sources had no input related to study design, data collection, or decision to submit for publication. (Davis Phinney Foundation; Parkinson's Disease Foundation; R01 NS077959 - National Institutes of Health; K12 HD055931 - National Institutes of Health; UL1 TR000448 - National Institutes of Health

Trolling in asynchronous computer-mediated communication: From user discussions to academic definitions

Whilst computer-mediated communication (CMC) can benefit users by providing quick and easy communication between those separated by time and space, it can also provide varying degrees of anonymity that may encourage a sense of impunity and freedom from being held accountable for inappropriate online behaviour. As such, CMC is a fertile ground for studying impoliteness, whether it occurs in response to perceived threat (flaming), or as an end in its own right (trolling). Currently, first and secondorder definitions of terms such as im/politeness (Brown and Levinson 1987; Bousfield 2008; Culpeper 2008; Terkourafi 2008), in-civility (Lakoff 2005), rudeness (Beebe 1995, Kienpointner 1997, 2008), and etiquette (Coulmas 1992), are subject to much discussion and debate, yet the CMC phenomenon of trolling is not adequately captured by any of these terms. Following Bousfield (in press), Culpeper (2010) and others, this paper suggests that a definition of trolling should be informed first and foremost by user discussions. Taking examples from a 172-million-word, asynchronous CMC corpus, four interrelated conditions of aggression, deception, disruption, and success are discussed. Finally, a working definition of trolling is presented

Esophageal Cancer Related Gene-4 Is a Choroid Plexus-Derived Injury Response Gene: Evidence for a Biphasic Response in Early and Late Brain Injury

By virtue of its ability to regulate the composition of cerebrospinal fluid (CSF), the choroid plexus (CP) is ideally suited to instigate a rapid response to traumatic brain injury (TBI) by producing growth regulatory proteins. For example, Esophageal Cancer Related Gene-4 (Ecrg4) is a tumor suppressor gene that encodes a hormone-like peptide called augurin that is present in large concentrations in CP epithelia (CPe). Because augurin is thought to regulate senescence, neuroprogenitor cell growth and differentiation in the CNS, we evaluated the kinetics of Ecrg4 expression and augurin immunoreactivity in CPe after CNS injury. Adult rats were injured with a penetrating cortical lesion and alterations in augurin immunoreactivity were examined by immunohistochemistry. Ecrg4 gene expression was characterized by in situ hybridization. Cell surface augurin was identified histologically by confocal microscopy and biochemically by sub-cellular fractionation. Both Ecrg4 gene expression and augurin protein levels were decreased 24–72 hrs post-injury but restored to uninjured levels by day 7 post-injury. Protein staining in the supraoptic nucleus of the hypothalamus, used as a control brain region, did not show a decrease of auguin immunoreactivity. Ecrg4 gene expression localized to CPe cells, and augurin protein to the CPe ventricular face. Extracellular cell surface tethering of 14 kDa augurin was confirmed by cell surface fractionation of primary human CPe cells in vitro while a 6–8 kDa fragment of augurin was detected in conditioned media, indicating release from the cell surface by proteolytic processing. In rat CSF however, 14 kDa augurin was detected. We hypothesize the initial release and proteolytic processing of augurin participates in the activation phase of injury while sustained Ecrg4 down-regulation is dysinhibitory during the proliferative phase. Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Synthesis and Characterization of Mono- and Di-O-Alkylated Derivatives of Methyl 3,5-Dihydroxy Benzoate

In the course of searching for monomers for larger macromolecular structures, we attempted the bis-O-alkylation of methyl 3,5-dihydroxy benzoate (1) with (bromomethyl)cyclohexane (2). To our knowledge, no literature procedures have been published on the preparation of ethers by alkylation of a phenol substrate with (bromomethyl)cyclohexane. We were surprised to find that the mono-O-alkylated product was predominantly obtained in this reaction. This finding is in contrast with those reported for alkylations, utilizing benzyl bromide where bis-O-alkylation is the predominant reaction (Yan et al. 2011). Herein we report a convenient synthesis of the bis-alkylated product 3 in good yield

The Early Effects of the Coronavirus Disease-19 Pandemic on Pediatric Resident Education: A National Assessment

PurposeResidency programs must ensure resident competence for independent practice. The coronavirus disease-19 (COVID-19) pandemic disrupted health care delivery, impacting pediatric residencies. This study examines the impact on pediatric resident education.MethodsThe authors conducted a mixed methods national survey of pediatric residency program directors (PDs) from May 2020 to July 2020. Data analysis included descriptive statistics, chi-square, and Wilcoxon rank sum tests. Multivariable modeling identified factors associated with resident preparation for more senior roles. Thematic analysis was performed on open-ended questions about PD COVID-19 pandemic recommendations to peers, Accreditation Council for Graduate Medical Education and American Board of Pediatrics.ResultsResponse rate was 55% (110/199). PDs reported the COVID-19 pandemic negatively affected inpatient (n&nbsp;=&nbsp;86, 78.2%), and outpatient education (n&nbsp;=&nbsp;104, 94.5%), procedural competence (n&nbsp;=&nbsp;64; 58.2%), and resident preparation for more senior roles (n&nbsp;=&nbsp;50, 45.5%). In bivariate analyses, increasingly negative impacts on inpatient and outpatient education were associated with an increasingly negative impact on resident preparation for more senior roles (P&nbsp;=&nbsp;.03, P&nbsp;=&nbsp;.008), these relationships held true in multivariable analysis. Qualitative analysis identified 4 themes from PD recommendations: 1) Clear communication from governing bodies and other leaders; 2) Flexibility within programs and from governing bodies; 3) Clinical exposure is key for competency development; 4) Online platforms are important for education, communication, and support.ConclusionsThe COVID-19 pandemic negatively impacted inpatient and outpatient education. When these were more negatively impacted, resident preparation for more senior roles was worse, highlighting the importance of competency based medical education to tailor experiences ensuring each resident is competent for independent practice

GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes

Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis