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Showing papers by "Rush University Medical Center published in 2019"


Journal ArticleDOI
01 May 2019-Nature
TL;DR: Single-cell transcriptomics from 48 individuals with varying degrees of Alzheimer's disease pathology demonstrates that gene-expression changes in Alzheimer’s disease are both cell-type specific and shared, and that transcriptional responses show sexual dimorphism.
Abstract: Alzheimer’s disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer’s disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer’s disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer’s disease. Single-cell transcriptomics from 48 individuals with varying degrees of Alzheimer’s disease pathology demonstrates that gene-expression changes in Alzheimer’s disease are both cell-type specific and shared, and that transcriptional responses show sexual dimorphism.

1,318 citations


Journal ArticleDOI
Eli A. Stahl1, Eli A. Stahl2, Gerome Breen3, Andreas J. Forstner  +339 moreInstitutions (107)
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

1,090 citations


Journal ArticleDOI
01 Jun 2019-Brain
TL;DR: A recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE).
Abstract: We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

753 citations


Journal ArticleDOI
Francine E. Garrett-Bakelman1, Francine E. Garrett-Bakelman2, Manjula Darshi3, Stefan J. Green4, Ruben C. Gur5, Ling Lin6, Brandon R. Macias, Miles J. McKenna7, Cem Meydan1, Tejaswini Mishra6, Jad Nasrini5, Brian D. Piening8, Brian D. Piening6, Lindsay F. Rizzardi9, Kumar Sharma3, Jamila H. Siamwala10, Jamila H. Siamwala11, Lynn Taylor7, Martha Hotz Vitaterna12, Maryam Afkarian13, Ebrahim Afshinnekoo1, Sara Ahadi6, Aditya Ambati6, Maneesh Arya, Daniela Bezdan1, Colin M. Callahan9, Songjie Chen6, Augustine M.K. Choi1, George E. Chlipala4, Kévin Contrepois6, Marisa Covington, Brian Crucian, Immaculata De Vivo14, David F. Dinges5, Douglas J. Ebert, Jason I. Feinberg9, Jorge Gandara1, Kerry George, John Goutsias9, George Grills1, Alan R. Hargens10, Martina Heer15, Martina Heer16, Ryan P. Hillary6, Andrew N. Hoofnagle17, Vivian Hook10, Garrett Jenkinson9, Garrett Jenkinson18, Peng Jiang12, Ali Keshavarzian19, Steven S. Laurie, Brittany Lee-McMullen6, Sarah B. Lumpkins, Matthew MacKay1, Mark Maienschein-Cline4, Ari Melnick1, Tyler M. Moore5, Kiichi Nakahira1, Hemal H. Patel10, Robert Pietrzyk, Varsha Rao6, Rintaro Saito20, Rintaro Saito10, Denis Salins6, Jan M. Schilling10, Dorothy D. Sears10, Caroline Sheridan1, Michael B. Stenger, Rakel Tryggvadottir9, Alexander E. Urban6, Tomas Vaisar17, Benjamin Van Espen10, Jing Zhang6, Michael G. Ziegler10, Sara R. Zwart21, John B. Charles, Craig E. Kundrot, Graham B. I. Scott22, Susan M. Bailey7, Mathias Basner5, Andrew P. Feinberg9, Stuart M. C. Lee, Christopher E. Mason, Emmanuel Mignot6, Brinda K. Rana10, Scott M. Smith, Michael Snyder6, Fred W. Turek12, Fred W. Turek11 
12 Apr 2019-Science
TL;DR: Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight.
Abstract: INTRODUCTION To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject. RATIONALE The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station. RESULTS Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function. CONCLUSION Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.

538 citations


Journal ArticleDOI
22 Oct 2019-JAMA
TL;DR: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function and management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.
Abstract: Importance Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.

530 citations


Journal ArticleDOI
TL;DR: Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize and should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
Abstract: Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

407 citations


Journal ArticleDOI
TL;DR: It is demonstrated that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease and that it is possibly associated with cognition.

356 citations


Journal ArticleDOI
TL;DR: This data indicates that BAs, products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria and seem dysregulated in Alzheimer's disease (AD).
Abstract: Introduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

322 citations


Journal ArticleDOI
TL;DR: A critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia and of current diagnostic and therapeutic approaches is provided to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.

317 citations


Journal ArticleDOI
TL;DR: It is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.
Abstract: Summary Gait impairments are among the most common and disabling symptoms of Parkinson's disease. Nonetheless, gait is not routinely assessed quantitatively but is described in general terms that are not sensitive to changes ensuing with disease progression. Quantifying multiple gait features (eg, speed, variability, and asymmetry) under natural and more challenging conditions (eg, dual-tasking, turning, and daily living) enhanced sensitivity of gait quantification. Studies of neural connectivity and structural network topology have provided information on the mechanisms of gait impairment. Advances in the understanding of the multifactorial origins of gait changes in patients with Parkinson's disease promoted the development of new intervention strategies, such as neurostimulation and virtual reality, aimed at alleviating gait impairments and enhancing functional mobility. For clinical applicability, it is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.

308 citations


Journal ArticleDOI
TL;DR: The authors show that bacterial tyrosine decarboxylases (TDC) decrease the levels of levodopa, the primary treatment in Parkinson’s disease, by conversion to dopamine, and suggest TDC as a potential predictive biomarker for treatment.
Abstract: Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson's disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson's disease patients.

Journal ArticleDOI
TL;DR: It is suggested that digital mental health interventions can be effective for improving depression, anxiety, and psychological well-being among college students, but more rigorous studies are needed to ascertain the effective elements of these interventions.
Abstract: Background: College students are increasingly reporting common mental health problems, such as depression and anxiety, and they frequently encounter barriers to seeking traditional mental health treatments. Digital mental health interventions, such as those delivered via the Web and apps, offer the potential to improve access to mental health treatment. Objective: This study aimed to review the literature on digital mental health interventions focused on depression, anxiety, and enhancement of psychological well-being among samples of college students to identify the effectiveness, usability, acceptability, uptake, and adoption of such programs. Methods: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (registration number CRD42018092800), and the search strategy was conducted by a medical research librarian in the following databases: MEDLINE (Ovid), EMBASE (Elsevier), PsycINFO (EbscoHost), the Cochrane Library (Wiley), and Web of Science (Thomson Reuters) from the date of inception to April 2019. Data were synthesized using a systematic narrative synthesis framework, and formal quality assessments were conducted to address the risk of bias. Results: A total of 89 studies met the inclusion criteria. The majority of interventions (71/89, 80%) were delivered via a website, and the most common intervention was internet-based cognitive behavioral therapy (28, 31%). Many programs (33, 37%) featured human support in the form of coaching. The majority of programs were either effective (42, 47%) or partially effective (30, 34%) in producing beneficial changes in the main psychological outcome variables. Approximately half of the studies (45, 51%) did not present any usability or acceptability outcomes, and few studies (4, 4%) examined a broad implementation of digital mental health interventions on college campuses. Quality assessments revealed a moderate-to-severe risk of bias in many of the studies. Conclusions: Results suggest that digital mental health interventions can be effective for improving depression, anxiety, and psychological well-being among college students, but more rigorous studies are needed to ascertain the effective elements of these interventions. Continued research on improving the user experience of, and thus user engagement with, these programs appears vital for the sustainable implementation of digital mental health interventions on college campuses.

Journal ArticleDOI
TL;DR: Continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo in patients with TRD in stable remission.
Abstract: Importance Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rankP = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rankP Conclusions and Relevance For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration ClinicalTrials.gov identifier:NCT02493868


Journal ArticleDOI
01 May 2019-Gut
TL;DR: It is suggested that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.
Abstract: Objective Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson’s disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration. Design To test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD. Results Patients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice. Conclusion Taken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.

Journal ArticleDOI
TL;DR: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation, and it is demonstrated that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations.
Abstract: PurposeApproximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non–small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical co...

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TL;DR: Outstanding questions about white matter hyperintensities and their relation to cognition, dementia, and AD are identified and answered to improve prevention and treatment of WMHs and dementia.

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TL;DR: In this paper, the authors focused on acute myocardial infarction (AMI) complicated by cardiogenic shock (AMICS) in cardiac intensive care units (CICUs).
Abstract: Background Clinical investigations of shock in cardiac intensive care units (CICUs) have primarily focused on acute myocardial infarction (AMI) complicated by cardiogenic shock (AMICS). Few studies...

Journal ArticleDOI
TL;DR: The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways, and summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.
Abstract: Ankylosing spondylitis (AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain; additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen (HLA)‑B27 and the interleukin‑23/17 axis. However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.

Journal ArticleDOI
TL;DR: Lower income households purchase less healthful foods compared with higher income households, suggesting that food purchasing patterns may mediate income differences in dietary intake quality.
Abstract: Lower household income has been consistently associated with poorer diet quality. Household food purchases may be an important intervention target to improve diet quality among low income populations. Associations between household income and the diet quality of household food purchases were examined. Food purchase receipt data were collected for 14 days from 202 urban households participating in a study about food shopping. Purchase data were analyzed using NDS-R software and scored using the Healthy Eating Index 2010 (HEI 2010). HEI total and subscores, and proportion of grocery dollars spent on food categories (e.g. fruits, vegetables, sugar sweetened beverages) were examined by household income-to-poverty ratio. Compared to lower income households, after adjusting for education, marital status and race, higher income households had significantly higher HEI total scores (mean [sd] = 68.2 [13.3] versus 51.6 [13.9], respectively, adjusted p = 0.05), higher total vegetable scores (mean [sd] = 3.6 [1.4] versus 2.3 [1.6], respectively, adjusted p < .01), higher dairy scores (mean [sd] = 5.6 [3.0] versus 5.0 [3.3], p = .05) and lower proportion of grocery dollars spent on frozen desserts (1% [.02] versus 3% [.07], respectively, p = .02). Lower income households purchase less healthful foods compared with higher income households. Food purchasing patterns may mediate income differences in dietary intake quality. ClinicalTrials.gov identifier: NCT02073643.

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TL;DR: The best predictor for falling outside the functional safe zone, both preoperatively and postoperatively, was femoral mobility, not the sagittal cup position (ie, cup anteinclination).
Abstract: Background The Lewinnek “safe zone” is not always predictive of stability after total hip arthroplasty (THA). Recent studies have focused on functional hip motion as observed on lateral spine-pelvis-hip x-rays. The purpose of this study was to assess the correlation between the Lewinnek safe zone and the functional safe zone based on hip and pelvic motion in the sagittal plane. Methods Three hundred twenty hips (291 patients) underwent primary THA using computer navigation. Two hundred ninety-six of these hips (92.5%) were within the Lewinnek safe zone as determined by inclination of 40° ± 10° and anteversion of 15° ± 10°. All patients had preoperative and postoperative standing and sitting lateral spinopelvic x-rays. The combined sagittal index (CSI), a combination of sagittal acetabular and femoral position, was measured for each patient and used to assess the functional safe zone. Data analysis was performed to identify hips in the Lewinnek safe zone inside and outside the sagittal functional safe zone. Predictive factors for hips outside the functional safe zone were identified. Results Of the 296 hips within the Lewinnek safe zone, 254 (85.8%) were also in the functional safe zone. Forty-two patients were outside the functional safe zone based on CSI; 19 had an increased standing CSI and 23 had a decreased sitting CSI, all were considered at risk for dislocation. Predictive factors for falling outside the functional safe zone were increased femoral mobility (P Conclusion In this study, 14.2% of hips within the Lewinnek safe zone were outside the functional safe zone, identifying a potential reason hips dislocate despite having “normal” cup angles. The best predictor for falling outside the functional safe zone, both preoperatively and postoperatively, was femoral mobility, not the sagittal cup position (ie, cup anteinclination). Level of Evidence Level III, retrospective review.

Journal ArticleDOI
TL;DR: A cross-sectional analysis of data from participants of the Rush Memory and Aging Project, a clinical-pathological cohort study of older adults without known dementia at baseline, found that frailty is related to both odds of Alzheimer's dementia and disease expression and has implications for clinical management.
Abstract: Summary Background Some people with substantial Alzheimer's disease pathology at autopsy had shown few characteristic clinical symptoms or signs of the disease, whereas others with little Alzheimer's disease pathology have been diagnosed with Alzheimer's dementia. We aimed to examine whether frailty, which is associated with both age and dementia, moderates the relationship between Alzheimer's disease pathology and Alzheimer's dementia. Methods We did a cross-sectional analysis of data from participants of the Rush Memory and Aging Project, a clinical–pathological cohort study of older adults (older than 59 years) without known dementia at baseline, living in Illinois, USA. Participants in the cohort study underwent annual neuropsychological and clinical evaluations. In the present cross-sectional analysis, we included those participants who did not have any form of dementia or who had Alzheimer's dementia at the time of their last clinical assessment and who had died and for whom complete autopsy data were available. Alzheimer's disease pathology was quantified by a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnosis of Alzheimer's dementia was based on clinician consensus. Frailty was operationalised retrospectively using health variable information obtained at each clincial evaluation using the deficit accumulation approach (41-item frailty index). Logistic regression and moderation modelling were used to assess relationships between Alzheimer's disease pathology, frailty, and Alzheimer's dementia. All analyses were adjusted for age, sex, and education. Findings Up to data cutoff (Jan 20, 2017), we included 456 participants (mean age at death 89·7 years [SD 6·1]; 316 [69%] women). 242 (53%) had a diagnosis of possible or probable Alzheimer's dementia at their last clinical assessment. Frailty (odds ratio 1·76, 95% CI 1·54–2·02; p Interpretation The degree of frailty among people of the same age modifies the association between Alzheimer's disease pathology and Alzheimer's dementia. That frailty is related to both odds of Alzheimer's dementia and disease expression has implications for clinical management, since individuals with even a low level of Alzheimer's disease pathology might be at risk for dementia if they have high amounts of frailty. Further research should assess how frailty and cognition change over time to better elucidate this complex relationship. Funding This study was funded by the Canadian Institutes of Health Research, including via the Canadian Collaboration on Neurodegeneration in Aging.

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TL;DR: This study establishes MCID, SCB, and PASS for ASES, Constant, and SANE scores in patients undergoing RCR and establishes lower preoperative scores were associated with achieving MCID and SCB and higher preoperative Constant scores associated with PASS.

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TL;DR: This paper identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank.
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

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TL;DR: The result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, is presented, which range from 0.1% to 30%, and $17,000 to $150,000.

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TL;DR: The risk of Alzheimer's dementia attributable to pathologic AD and 8 other neuropathologies is examined and it is found that Alzheimer's disease is more likely to be diagnosed after certain neuropathological events than after others.
Abstract: Objective The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to pathologic AD and 8 other neuropathologies. Methods Participants (n = 1,161) came from 2 clinical-pathological studies of aging. Multivariable logistic regression models examined associations of 8 neuropathological indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Furthermore, because some dementia cases are not driven by common neuropathologies, we re-estimated the attributable risks after empirically adjusting for such cases. Results Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at time of death. With the exception of microinfarcts, all neuropathological indices were independently associated with greater odds of Alzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases were attributable to pathological AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to transactive response DNA-binding protein 43, 8.1% to cerebral amyloid angiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all 8 indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all 8 neuropathologic indices combined. Interpretation Pathological AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two-thirds of Alzheimer's dementia cases are attributable to common age-related neuropathologies, suggesting that other disease and resilience factors are important. ANN NEUROL 2019;85:114-124.

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TL;DR: A first-in-man clinical trial was completed with VentriGel, an extracellular matrix hydrogel derived from decellularized porcine myocardium, in post-MI patients as mentioned in this paper.

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30 Jan 2019
TL;DR: This dataset is intended to be used for machine learning and is composed of annotations with bounding boxes for pulmonary opacity on chest radiographs which may represent pneumonia in the appropriate clinical setting.
Abstract: This dataset is intended to be used for machine learning and is composed of annotations with bounding boxes for pulmonary opacity on chest radiographs which may represent pneumonia in the appropria...

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TL;DR: Gremlin-1 is identified as a mechanical loading-inducible factor in chondrocytes, detected at high levels in middle and deep layers of cartilage after cyclic strain or hydrostatic pressure loading, and contributing to osteoarthritis via activation of the NF-κB pathway.
Abstract: Exposure of articular cartilage to excessive mechanical loading is deeply involved in the pathogenesis of osteoarthritis. Here, we identify gremlin-1 as a mechanical loading-inducible factor in chondrocytes, detected at high levels in middle and deep layers of cartilage after cyclic strain or hydrostatic pressure loading. Gremlin-1 activates nuclear factor-κB signalling, leading to subsequent induction of catabolic enzymes. In mice intra-articular administration of gremlin-1 antibody or chondrocyte-specific deletion of Gremlin-1 decelerates osteoarthritis development, while intra-articular administration of recombinant gremlin-1 exacerbates this process. Furthermore, ras-related C3 botulinum toxin substrate 1 activation induced by mechanical loading enhances reactive oxygen species (ROS) production. Amongst ROS-activating transcription factors, RelA/p65 induces Gremlin-1 transcription, which antagonizes induction of anabolic genes such as Sox9, Col2a1, and Acan by bone morphogenetic proteins. Thus, gremlin-1 plays essential roles in cartilage degeneration by excessive mechanical loading.

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TL;DR: Biventricular pacing (BiV) is established as the primary modality to achieve cardiac resynchronization therapy (CRT), although nonresponse rates approach 30% to 40% as discussed by the authors.