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Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares

Azzouz, Doua F; Chen, Ze; Izmirly, Peter M; Chen, Lea Ann; Li, Zhi; Zhang, Chongda; Mieles, David; Trujillo, Kate; Heguy, Adriana; Pironti, Alejandro; Putzel, Greg G; Schwudke, Dominik; Fenyo, David; Buyon, Jill P; Alekseyenko, Alexander V; Gisch, Nicolas; Silverman, Gregg J
OBJECTIVE:Whereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities. METHODS:In an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed. RESULTS:(RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares. CONCLUSIONS:Our findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients.
PMID: 37365013
ISSN: 1468-2060
CID: 5540152

A phylogenetic approach for weighting genetic sequences

De Maio, Nicola; Alekseyenko, Alexander V; Coleman-Smith, William J; Pardi, Fabio; Suchard, Marc A; Tamuri, Asif U; Truszkowski, Jakub; Goldman, Nick
BACKGROUND:Many important applications in bioinformatics, including sequence alignment and protein family profiling, employ sequence weighting schemes to mitigate the effects of non-independence of homologous sequences and under- or over-representation of certain taxa in a dataset. These schemes aim to assign high weights to sequences that are 'novel' compared to the others in the same dataset, and low weights to sequences that are over-represented. RESULTS:We formalise this principle by rigorously defining the evolutionary 'novelty' of a sequence within an alignment. This results in new sequence weights that we call 'phylogenetic novelty scores'. These scores have various desirable properties, and we showcase their use by considering, as an example application, the inference of character frequencies at an alignment column-important, for example, in protein family profiling. We give computationally efficient algorithms for calculating our scores and, using simulations, show that they are versatile and can improve the accuracy of character frequency estimation compared to existing sequence weighting schemes. CONCLUSIONS:Our phylogenetic novelty scores can be useful when an evolutionarily meaningful system for adjusting for uneven taxon sampling is desired. They have numerous possible applications, including estimation of evolutionary conservation scores and sequence logos, identification of targets in conservation biology, and improving and measuring sequence alignment accuracy.
PMCID:8164272
PMID: 34049487
ISSN: 1471-2105
CID: 4890552

Using Flow Disruptions to Examine System Safety in Robotic-Assisted Surgery: Protocol for a Stepped Wedge Crossover Design

Alfred, Myrtede C; Cohen, Tara N; Cohen, Kate A; Kanji, Falisha F; Choi, Eunice; Del Gaizo, John; Nemeth, Lynne S; Alekseyenko, Alexander V; Shouhed, Daniel; Savage, Stephen J; Anger, Jennifer T; Catchpole, Ken
BACKGROUND:The integration of high technology into health care systems is intended to provide new treatment options and improve the quality, safety, and efficiency of care. Robotic-assisted surgery is an example of high technology integration in health care, which has become ubiquitous in many surgical disciplines. OBJECTIVE:This study aims to understand and measure current robotic-assisted surgery processes in a systematic, quantitative, and replicable manner to identify latent systemic threats and opportunities for improvement based on our observations and to implement and evaluate interventions. This 5-year study will follow a human factors engineering approach to improve the safety and efficiency of robotic-assisted surgery across 4 US hospitals. METHODS:The study uses a stepped wedge crossover design with 3 interventions, introduced in different sequences at each of the hospitals over four 8-month phases. Robotic-assisted surgery procedures will be observed in the following specialties: urogynecology, gynecology, urology, bariatrics, general, and colorectal. We will use the data collected from observations, surveys, and interviews to inform interventions focused on teamwork, task design, and workplace design. We intend to evaluate attitudes toward each intervention, safety culture, subjective workload for each case, effectiveness of each intervention (including through direct observation of a sample of surgeries in each observational phase), operating room duration, length of stay, and patient safety incident reports. Analytic methods will include statistical data analysis, point process analysis, and thematic content analysis. RESULTS:The study was funded in September 2018 and approved by the institutional review board of each institution in May and June of 2019 (CSMC and MDRH: Pro00056245; VCMC: STUDY 270; MUSC: Pro00088741). After refining the 3 interventions in phase 1, data collection for phase 2 (baseline data) began in November 2019 and was scheduled to continue through June 2020. However, data collection was suspended in March 2020 due to the COVID-19 pandemic. We collected a total of 65 observations across the 4 sites before the pandemic. Data collection for phase 2 was resumed in October 2020 at 2 of the 4 sites. CONCLUSIONS:This will be the largest direct observational study of surgery ever conducted with data collected on 680 robotic surgery procedures at 4 different institutions. The proposed interventions will be evaluated using individual-level (workload and attitude), process-level (perioperative duration and flow disruption), and organizational-level (safety culture and complications) measures. An implementation science framework is also used to investigate the causes of success or failure of each intervention at each site and understand the potential spread of the interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)/UNASSIGNED:DERR1-10.2196/25284.
PMID: 33560239
ISSN: 1929-0748
CID: 4779572

A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD

Sofi, M Hanief; Wu, Yongxia; Ticer, Taylor; Schutt, Steven; Bastian, David; Choi, Hee-Jin; Tian, Linlu; Mealer, Corey; Liu, Chen; Westwater, Caroline; Armeson, Kent E; Alekseyenko, Alexander V; Yu, Xue-Zhong
Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT.
PMID: 33554953
ISSN: 2379-3708
CID: 4779332

Each patient is a research biorepository: informatics-enabled research on surplus clinical specimens via the living BioBank

Alekseyenko, Alexander V; Hamidi, Bashir; Faith, Trevor D; Crandall, Keith A; Powers, Jennifer G; Metts, Christopher L; Madory, James E; Carroll, Steven L; Obeid, Jihad S; Lenert, Leslie A
The ability to analyze human specimens is the pillar of modern-day translational research. To enhance the research availability of relevant clinical specimens, we developed the Living BioBank (LBB) solution, which allows for just-in-time capture and delivery of phenotyped surplus laboratory medicine specimens. The LBB is a system-of-systems integrating research feasibility databases in i2b2, a real-time clinical data warehouse, and an informatics system for institutional research services management (SPARC). LBB delivers deidentified clinical data and laboratory specimens. We further present an extension to our solution, the Living µBiome Bank, that allows the user to request and receive phenotyped specimen microbiome data. We discuss the details of the implementation of the LBB system and the necessary regulatory oversight for this solution. The conducted institutional focus group of translational investigators indicates an overall positive sentiment towards potential scientific results generated with the use of LBB. Reference implementation of LBB is available at https://LivingBioBank.musc.edu.
PMID: 33166379
ISSN: 1527-974x
CID: 4664842

Evidence for Differentiation of Colon Tissue Microbiota in Patients with and without Postoperative Hirschsprung's Associated Enterocolitis: A Pilot Study

Arbizu, Ricardo A; Collins, David; Wilson, Robert C; Alekseyenko, Alexander V
Purpose/UNASSIGNED:To investigate the differences in the colon microbiota composition of Hirschsprung's disease (HSCR) patients with and without a history of postoperative Hirschsprung's associated enterocolitis (HAEC). Methods/UNASSIGNED:Colon tissue microbiota was characterized by bacterial deoxyribonucleic acid (DNA) extraction and 16S rDNA sequencing for taxonomic classification and comparison. Results/UNASSIGNED:in HSCR patients. Conclusion/UNASSIGNED:Our findings provide evidence that the colon tissue microbiota composition is different in HSCR patients with and without postoperative HAEC.
PMCID:7813566
PMID: 33505891
ISSN: 2234-8646
CID: 4767422

Research and Exploratory Analysis Driven-Time-data Visualization (read-tv) software

Del Gaizo, John; Catchpole, Ken R; Alekseyenko, Alexander V
Motivation/UNASSIGNED:provides unique filtering and changepoint analysis (CPA) features. The need for these analyses was motivated by research of surgical work-flow disruptions in operating room settings. Specifically, for the analysis of the causes and characteristics of periods of high disruption-rates, which are associated with adverse surgical outcomes. Materials and Methods/UNASSIGNED:generates and evaluates code to filter and visualize data. Users can view the visualization code from within the application, which facilitates reproducibility. The data input requirements are simple, a table with a time column with no missing values. The input can either be in the form of a file, or an in-memory dataframe- which is effective for rapid visualization during curation. Results/UNASSIGNED:to automatically detect surgical disruption cascades. We found that the most common disruption type during a cascade was training, followed by equipment. Discussion/UNASSIGNED:, it is relatively simple to add new functionality by implementing a tab in the source code. Conclusion/UNASSIGNED:enables quick identification of patterns through customizable longitudinal plots; faceting; CPA; and user-specified filters. The package is available on GitHub under an MIT license.
PMCID:7935610
PMID: 33709063
ISSN: 2574-2531
CID: 4809552

Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans

Wallace, Kristin; Nahhas, Georges J; Bookhout, Christine; Lewin, David N; Paulos, Chrystal M; Nikolaishvili-Feinberg, Nana; Cohen, Stephanie M; Guglietta, Silvia; Bakhtiari, Ali; Camp, E Ramsay; Hill, Elizabeth G; Baron, John A; Wu, Jennifer D; Alekseyenko, Alexander V
Background/UNASSIGNED:African Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease. Methods/UNASSIGNED:. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch. Results/UNASSIGNED:CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001). Conclusions/UNASSIGNED:CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.
PMCID:8112239
PMID: 33987094
ISSN: 2234-943x
CID: 4867782

The Influences of Bioinformatics Tools and Reference Databases in Analyzing the Human Oral Microbial Community

Sierra, Maria A; Li, Qianhao; Pushalkar, Smruti; Paul, Bidisha; Sandoval, Tito A; Kamer, Angela R; Corby, Patricia; Guo, Yuqi; Ruff, Ryan Richard; Alekseyenko, Alexander V; Li, Xin; Saxena, Deepak
There is currently no criterion to select appropriate bioinformatics tools and reference databases for analysis of 16S rRNA amplicon data in the human oral microbiome. Our study aims to determine the influence of multiple tools and reference databases on α-diversity measurements and β-diversity comparisons analyzing the human oral microbiome. We compared the results of taxonomical classification by Greengenes, the Human Oral Microbiome Database (HOMD), National Center for Biotechnology Information (NCBI) 16S, SILVA, and the Ribosomal Database Project (RDP) using Quantitative Insights Into Microbial Ecology (QIIME) and the Divisive Amplicon Denoising Algorithm (DADA2). There were 15 phyla present in all of the analyses, four phyla exclusive to certain databases, and different numbers of genera were identified in each database. Common genera found in the oral microbiome, such as Veillonella, Rothia, and Prevotella, are annotated by all databases; however, less common genera, such as Bulleidia and Paludibacter, are only annotated by large databases, such as Greengenes. Our results indicate that using different reference databases in 16S rRNA amplicon data analysis could lead to different taxonomic compositions, especially at genus level. There are a variety of databases available, but there are no defined criteria for data curation and validation of annotations, which can affect the accuracy and reproducibility of results, making it difficult to compare data across studies.
PMID: 32756341
ISSN: 2073-4425
CID: 4554112

The Gut Microbiome and Xenobiotics: Identifying Knowledge Gaps

Sutherland, Vicki L; McQueen, Charlene A; Mendrick, Donna; Gulezian, Donna; Cerniglia, Carl; Foley, Steven; Forry, Sam; Khare, Sangeeta; Liang, Xue; Manautou, Jose E; Tweedie, Donald; Young, Howard; Alekseyenko, Alexander V; Burns, Frank; Dietert, Rod; Wilson, Alan; Chen, Connie
There is an increasing awareness that the gut microbiome plays a critical role in human health and disease, but mechanistic insights are often lacking. In June 2018, the Health and Environmental Sciences Institute (HESI) held a workshop, "The Gut Microbiome: Markers of Human Health, Drug Efficacy and Xenobiotic Toxicity" (https://hesiglobal.org/event/the-gut-microbiome-workshop) to identify data gaps in determining how gut microbiome alterations may affect human health. Speakers and stakeholders from academia, government, and industry addressed multiple topics including the current science on the gut microbiome, endogenous and exogenous metabolites, biomarkers, and model systems. The workshop presentations and breakout group discussions formed the basis for identifying data gaps and research needs. Two critical issues that emerged were defining the microbial composition and function related to health and developing standards for models, methods and analysis in order to increase the ability to compare and replicate studies. A series of key recommendations were formulated to focus efforts to further understand host-microbiome interactions and the consequences of exposure to xenobiotics as well as identifying biomarkers of microbiome-associated disease and toxicity.
PMID: 32658296
ISSN: 1096-0929
CID: 4526982