Research Spotlight

Cougnoux, A., R. A. Drummond, M. Fellmeth, F. Navid, A. L. Collar, J. Iben, A. B. Kulkarni, J. Pickel, R. Schiffmann, C. A. Wassif, N. X. Cawley, M. S. Lionakis and F. D. Porter (2019). “Unique molecular signature in mucolipidosis type IV microglia.” J Neuroinflammation 16(1): 276.

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BACKGROUND: Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS: We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1(-/-)) and Fabry disease (Gla(y/-)) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS: We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1(-/-) microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1(-/-) microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer’s disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in “disease-associated microglia” pattern among these diseases. CONCLUSIONS: The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.

Cole, M., K. Froehlich-Grobe, S. Driver, R. Shegog and J. McLaughlin (2019). “Website Redesign of a 16-Week Exercise Intervention for People With Spinal Cord Injury by Using Participatory Action Research.” JMIR Rehabil Assist Technol 6(2): e13441.

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BACKGROUND: People with spinal cord injury (SCI) are at higher risk for numerous preventable chronic conditions. Physical activity is a protective factor that can reduce this risk, yet those with SCI encounter barriers to activity and are significantly less likely to be active. Limited evidence supports approaches to promote increased physical activity for those with SCI. OBJECTIVE: Building upon our previous theory- and evidence-based approach to increase participation in regular physical activity for those with SCI, this study aimed to use a participatory action research approach to translate a theory-based intervention to be delivered via the Web to individuals with SCI. METHODS: A total of 10 individuals with SCI were invited to participate in consumer input meetings to provide the research team with iterative feedback on an initial website designed as a platform for delivering a theory-based exercise intervention. RESULTS: A total of 7 individuals with SCI whose average age was 43.6 years (SD 13.4) and lived an average age of 12.5 years (SD 14.9) with SCI met on 2 occasions to provide their feedback of the website platform, both on the initial design and subsequently on the revamped site. Their iterative feedback resulted in redesigning the website content, format, and functionality as well as delivery of the intervention program. CONCLUSIONS: The substantially redesigned website offers an easier-to-navigate platform for people with SCI with greater functionality that delivers information using a module format with less text, short video segments, and presents more resources. Preliminary testing of the site is the next step.

Chhatriwalla, A. K., S. Vemulapalli, M. Szerlip, S. Kodali, R. T. Hahn, J. T. Saxon, M. J. Mack, G. Ailawadi, J. Rymer, P. Manandhar, A. S. Kosinski and P. Sorajja (2019). “Operator Experience and Outcomes of Transcatheter Mitral Valve Repair in the United States.” J Am Coll Cardiol 74(24): 2955-2965.

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BACKGROUND: Transcatheter mitral valve repair (TMVr) for the treatment of mitral regurgitation (MR) is a complex procedure that requires development of a unique skillset. OBJECTIVES: The purpose of this study was to examine the relationship between operator experience and procedural results of TMVr. METHODS: TMVr device procedures from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry were analyzed with operator case number as a continuous and categorical (1 to 25, 26 to 50, and >50) variable. Outcomes of procedural success, procedural time, and in-hospital procedural complications were examined. The learning curve for the procedure was evaluated using generalized linear mixed models adjusting for baseline clinical variables. RESULTS: All TMVr device procedures (n = 14,923) performed by 562 operators at 290 sites between November 2013 and March 2018 were analyzed. Optimal procedural success (less-than-or-equal-to 1+ residual MR without death or cardiac surgery) increased across categories of operator experience (63.9%, 68.4%, and 75.1%; p < 0.001), while procedural time and procedural complications decreased. Acceptable procedural success (less-than-or-equal-to 2+ residual MR without death or cardiac surgery) also increased with operator experience, but the differences were smaller (91.4%, 92.4%, and 93.8%; p < 0.001). These associations remained significant in adjusted, continuous variable analyses. Visual inflection points in the learning curves for procedural time, procedural success, and procedural complications were evident after approximately 50 cases, with continued improvements observed out to 200 cases. CONCLUSIONS: For TMVr device procedures, operator experience was associated with improvements in procedural success, procedure time, and procedural complications. The effect of operator experience was greater when considering the goal of achieving 1+ residual MR.

Carl, E., S. M. Witcraft, B. Y. Kauffman, E. M. Gillespie, E. S. Becker, P. Cuijpers, M. Van Ameringen, J. A. J. Smits and M. B. Powers (2020). “Psychological and pharmacological treatments for generalized anxiety disorder (GAD): a meta-analysis of randomized controlled trials.” Cogn Behav Ther 49(1): 1-21.

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The purpose of this meta-analysis was to provide updated pooled effect sizes of evidence-based psychotherapies and medications for generalized anxiety disorder (GAD) and to investigate potential moderators of outcomes. Seventy-nine randomized controlled trials (RCT) including 11,002 participants with a diagnosis of GAD were included in a meta-analysis that tested the efficacy of psychotherapies or medications for GAD. Psychotherapy showed a medium to large effect size (g = 0.76) and medication showed a small effect size (g = 0.38) on GAD outcomes. Psychotherapy also showed a medium effect on depression outcomes (g = 0.64) as did medications (g = 0.59). Younger age was associated with a larger effect size for psychotherapy (p < 0.05). There was evidence of publication bias in psychotherapy studies. This analysis found a medium to large effect for empirically supported psychotherapy interventions on GAD outcomes and a small effect for medications on GAD outcomes. Both groups showed a medium effect on depression outcomes. Because medication studies had more placebo control conditions than inactive conditions compared to psychotherapy studies, effect sizes between the domains should not be compared directly. Patient age should be further investigated as a potential moderator in psychotherapy outcomes in GAD.

Callewaert, C., T. Nakatsuji, R. Knight, T. Kosciolek, A. Vrbanac, P. Kotol, M. Ardeleanu, T. Hultsch, E. Guttman-Yassky, R. Bissonnette, J. I. Silverberg, J. Krueger, A. Menter, N. M. H. Graham, G. Pirozzi, J. D. Hamilton and R. L. Gallo (2020). “IL-4Ralpha Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.” J Invest Dermatol 140(1): 191-202.e197.

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Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.