ABSTRACT
BACKGROUND: The novel coronavirus disease (COVID-19) has had a significant impact on orthopedic surgery practice, but there has been little investigation of the effects of COVID-19 on the orthopedic surgery literature. Additionally, because orthopedic research plays a vital role in physician education, changes to the characteristics and content of published literature can have lasting impacts on future teaching and learning. This paper represents the first known analysis of the COVID-19 pandemic's impact on peer-reviewed articles published in orthopedic surgery journals. METHODS: The 20 orthopedic journals with the highest impact factors in 2019, according to the Journal Citation Reports, were included in this study. Using PubMed and COVID-19 related keywords as well as manual screening, a final count of 199 articles were assessed for this study and subsequently sorted by country of origin, orthopedic subspecialty, article type, and general theme. Kruskal Wallis and Pearson's Chi-squared tests were used to analyze continuous and categorical variables, respectively. RESULTS: Fourteen journals published articles relating to COVID-19, representing 26 countries with the United States (37%) and United Kingdom (13%) publishing the greatest proportion of all COVID-19 articles. Sixty percent of publications discussed COVID-19's impact on the overall field of orthopedic surgery, with the remainder focusing on specific subspecialties. Forty-seven percent of publications were original research articles while 46% were editorials or commentaries. The median time to publication for all COVID-19 related articles was 24.5 days, compared to the 129 days reported for orthopedic journals prior to the COVID-19 pandemic (p < 0.001). In the first 100 articles published, 49% (n = 49) originated exclusively from United States institutions, whereas only 25% (n = 25) of the next ninety-nine articles had US-only institutions (p < 0.001). CONCLUSIONS: The COVID-19 pandemic has significantly impacted the characteristics, content, and time to publication of the orthopedic surgery literature. The data and ideas presented in this paper should help streamline future, formal analysis on the lasting implications of COVID-19 on orthopedic surgery practice, teaching, and learning.
ABSTRACT
Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.
Subject(s)
Astrocytes/metabolism , Glucosylceramidase/genetics , Neurons/metabolism , Parkinsonian Disorders/genetics , Protein Aggregation, Pathological/genetics , alpha-Synuclein/metabolism , Animals , Astrocytes/cytology , Astrocytes/pathology , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Disease Susceptibility , Genetic Predisposition to Disease , Glucosylceramidase/metabolism , HEK293 Cells , Hippocampus/cytology , Hippocampus/metabolism , Hippocampus/pathology , Humans , Lewy Body Disease/genetics , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Mesencephalon/cytology , Mesencephalon/metabolism , Mesencephalon/pathology , Mice , Mice, Transgenic , Neurons/cytology , Neurons/pathology , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Primary Cell Culture , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology , Synucleinopathies/genetics , Synucleinopathies/metabolism , Synucleinopathies/pathologyABSTRACT
Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the most common causes of familial Parkinson's disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. LRRK2 is therefore a prime candidate for small molecule kinase inhibitor development. However, it is currently unknown how LRRK2 influences the underlying pathogenesis of PD and how LRRK2 might influence extant pathogenesis. To understand whether LRRK2 inhibition would show some benefit in the absence of LRRK2 mutations, we treated a preclinical mouse model of PD with the potent LRRK2 inhibitor MLi-2. The inhibitor was well-tolerated by mice and dramatically reduced LRRK2 kinase activity. However, LRRK2 inhibition did not reverse motor phenotypes, pathological α-synuclein accumulation or neuron loss. The current study suggests that LRRK2 is not necessary for α-synuclein pathogenesis in this mouse model of PD and that further studies are needed to assess the likely clinical benefit of LRRK2 inhibition in idiopathic PD.
