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Comparison of Plasma Oxalate Measurement Methods in Patients With End-Stage Kidney Disease
Jaber, Karim; Zaidan, Nadim; Pierce, Kerry; Kim, Sooran; Xiong, Xiaozhong; Ruggles, Kelly; Clish, Clary; Li, Huilin; Nazzal, Lama
PMCID:12231001
PMID: 40630270
ISSN: 2468-0249
CID: 5890822
Right-Sided Dysplasia in Inflammatory Bowel Disease Is Not Associated with Conventional Risk Factors for Neoplasia
Bhattacharya, Sumona; Beaty, William; Faye, Adam S; Axelrad, Jordan E
INTRODUCTION/UNASSIGNED:In the general population, right I-sided dysplasia presents a higher risk for colorectal cancer (CRC) and metachronous dysplasia compared to left (L)-sided dysplasia. Given that patients with inflammatory bowel disease (IBD) are at higher risk for dysplasia than the general population, we sought to assess the risk factors as well as the differences in outcomes between patients with R-sided, L-sided, and both R- and L-sided dysplasia. METHODS/UNASSIGNED:A retrospective chart review was performed on patients at NYU Langone Health who had evidence of dysplasia on a colonoscopy between 2011 and 2021. Demographics and pertinent medical history were compiled. Cohorts were based on the dysplasia location (R-sided, L-sided, or R- and L-sided) and the IBD-related outcomes were analyzed. RESULTS/UNASSIGNED:= 0.03). CONCLUSIONS/UNASSIGNED:Patients with UC had a higher risk for L-sided colonic dysplasia compared to patients with CD; however, there were no differences in the progression of dysplasia between those who had R-sided and those who had L-sided dysplasia. Larger studies are needed to assess the risk factors and outcomes related to the laterality of dysplasia and further validate these findings among patients with IBD.
PMCID:11999668
PMID: 40242653
ISSN: 2036-7414
CID: 5828542
Evaluating Methods for Imputing Race and Ethnicity in Electronic Health Record Data
Conderino, Sarah; Divers, Jasmin; Dodson, John A; Thorpe, Lorna E; Weiner, Mark G; Adhikari, Samrachana
OBJECTIVE:To compare anonymized and non-anonymized approaches for imputing race and ethnicity in descriptive studies of chronic disease burden using electronic health record (EHR)-based datasets. STUDY SETTING AND DESIGN/METHODS:In this New York City-based study, we first conducted simulation analyses under different missing data mechanisms to assess the performance of Bayesian Improved Surname Geocoding (BISG), single imputation using neighborhood majority information, random forest imputation, and multiple imputation with chained equations (MICE). Imputation performance was measured using sensitivity, precision, and overall accuracy; agreement with self-reported race and ethnicity was measured with Cohen's kappa (κ). We then applied these methods to impute race and ethnicity in two EHR-based data sources and compared chronic disease burden (95% CIs) by race and ethnicity across imputation approaches. DATA SOURCES AND ANALYTIC SAMPLE/UNASSIGNED:Our data sources included EHR data from NYU Langone Health and the INSIGHT Clinical Research Network from 3/6/2016 to 3/7/2020 extracted for a parent study on older adults in NYC with multiple chronic conditions. PRINCIPAL FINDINGS/RESULTS: = 0.33). When these methods were applied to the NYU and INSIGHT cohorts, however, racial and ethnic distributions and chronic disease burden were consistent across all imputation methods. Slight improvements in the precision of estimates were observed under all imputation approaches compared to a complete case analysis. CONCLUSIONS:BISG imputation may provide a more accurate racial and ethnic classification than single or multiple imputation using anonymized covariates, particularly if the missing data mechanism is MNAR. Descriptive studies of disease burden may not be sensitive to methods for imputing missing data.
PMID: 40421571
ISSN: 1475-6773
CID: 5855152
Unravelling cysteine-deficiency-associated rapid weight loss
Varghese, Alan; Gusarov, Ivan; Gamallo-Lana, Begoña; Dolgonos, Daria; Mankan, Yatin; Shamovsky, Ilya; Phan, Mydia; Jones, Rebecca; Gomez-Jenkins, Maria; White, Eileen; Wang, Rui; Jones, Drew R; Papagiannakopoulos, Thales; Pacold, Michael E; Mar, Adam C; Littman, Dan R; Nudler, Evgeny
Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.
PMID: 40399674
ISSN: 1476-4687
CID: 5853222
Machine learning approach to single cell transcriptomic analysis of Sjogren's disease reveals altered activation states of B and T lymphocytes
McDermott, Maxwell; Li, Wenyi; Wang, Yin-Hu; Chen, Allen Y; Lacruz, Rodrigo; Nadorp, Bettina; Feske, Stefan
Sjogren's Disease (SjD) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction and immune cell infiltration leading to gland inflammation and destruction. Although SjD is a common disease, its pathogenesis is not fully understood. In this study, we conducted a single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMC) from patients with SjD and symptomatic non-SjD controls to identify cell types and functional changes involved in SjD pathogenesis. All PBMCs populations showed marked differences in gene expression between SjD patients and controls, particularly an increase in interferon (IFN) signaling gene signatures. T and B cells of SjD patients displayed a depletion of ribosomal gene expression and pathways linked to protein translation. SjD patients had increased frequencies of naive B cells, which featured a unique gene expression profile (GEP) distinct from controls and had hallmarks of B cell hyperactivation. Non-negative matrix factorization (NMF) also identified several non-overlapping GEPs in CD4+ and CD8+ T cells with differential usage in SjD patients and controls. Of these, only the Th1 activation GEP was enriched in T cells of SjD patients whereas the other two GEPs were depleted in T cells, emphasizing the important role of Th1 cells in SjD. Our study provides evidence for aberrant and unique gene expression patterns in both B and T lymphocytes of SjD patients that point to their altered activation states and may provide new insights into the pathogenesis of SjD.
PMID: 40318561
ISSN: 1095-9157
CID: 5834802
"I'm his brain": A qualitative study of care partners supporting the inner strength of persons living with mild cognitive impairment
Morgan, Brianna; Brody, Abraham A; Chodosh, Joshua; Karlawish, Jason; Ravitch, Sharon; Massimo, Lauren; Hodgson, Nancy
BACKGROUND:Despite the need, care partners of persons living with mild cognitive impairment (MCI) use supportive services less. The unique needs of care partners to persons living with MCI are not well described. This study explores how care partners support the inner strength of persons newly diagnosed with MCI. METHODS:Nine dyads of persons living with MCI and their care partners completed semi-structured interviews, analyzed according to the Listening Guide methodology. RESULTS:Care partners described supporting inner strengths of persons living with MCI by carrying the cognitive load and being reliable. Reconceptualizing identity was foundational. Across themes, care partners needed simultaneous support for themselves. DISCUSSION/CONCLUSIONS:This study represents the perspectives of a well-defined group of care partners to persons living with MCI. Eliciting the perspectives of underrepresented care partners and equitable access to MCI diagnosis are essential for future research. Dyadic supportive services tailored for MCI using a strengths-based approach are needed. HIGHLIGHTS/CONCLUSIONS:Care partners to persons living with mild cognitive impairment (MCI) are unique. Care partners support inner strength of persons living with MCI and need simultaneous support. Care partners reconceptualize their identities, are reliable, and carry cognitive load. Methods for eliciting perspectives of underrepresented care partners are needed. Supportive services tailored for MCI using a strengths-based approach are needed.
PMCID:12089077
PMID: 40390201
ISSN: 1552-5279
CID: 5852912
Program of intensive support in emergency departments for care partners of cognitively impaired patients: A randomized controlled trial
Chodosh, Joshua; Fowler, Nicole R; Perkins, Anthony J; Connor, Karen I; Messina, Frank; Boustani, Malaz; Borson, Soo
INTRODUCTION/BACKGROUND:Reasons for emergency department (ED) visits for persons with cognitive impairment are usually driven by unmet needs. METHODS:ED patients ≥ 75 years old with screener-detected cognitive impairment (Mini-Cog ≤ 3/5) or care partner tool (Informant Questionnaire on Cognitive Decline in the Elderly > 3.4), and care partners from New York and Indiana academically affiliated EDs, were randomly assigned to 6-month dementia care management or usual care. Nurses and paraprofessionals used principles of dementia care management informed by root cause analyses of participants' ED visits. We used logistic regression to compare ED revisit rates during the 6-month intervention. RESULTS:Of 642 dyads-320 intervention, 322 usual care-256 of 632 (40.5%) had at least one ED revisit within 6 months of index visit, but without between-group differences in revisit rates, care partner activation, or symptoms of depression or anxiety at 3 or 6 months. DISCUSSION/CONCLUSIONS:Using root cause analysis to inform dementia care management did not reduce ED revisits. HIGHLIGHTS/CONCLUSIONS:Cognitive screening during emergency department (ED) visits is feasible for quality improvement. ED cognitive screening alone may not identify dyads who need care management. Identifying root causes for ED visits could personalize post-visit care management. Root cause-informed care management did not reduce ED revisits. Need-based screening might better target ED patients with cognitive impairment.
PMCID:12094886
PMID: 40399761
ISSN: 1552-5279
CID: 5853242
Stabilization of GTSE1 by cyclin D1-CDK4/6-mediated phosphorylation promotes cell proliferation with implications for cancer prognosis
García-Vázquez, Nelson; González-Robles, Tania J; Lane, Ethan; Spasskaya, Daria; Zhang, Qingyue; Kerzhnerman, Marc A; Jeong, YeonTae; Collu, Marta; Simoneschi, Daniele; Ruggles, Kelly V; Róna, Gergely; Kaisari, Sharon; Pagano, Michele
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1-CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1's role in cell cycle control and oncogenesis beyond RB phosphorylation.
PMID: 40272409
ISSN: 2050-084x
CID: 5830502
Spontaneous Ileitis and Post-Surgical Murine Models of Enteric Hyperoxaluria
Jaber, Karim; Zaidan, Nadim; Ho, Melody; Xiong, Xiaozhong; Mishra, Rashmi; Nair, Ambika; Mishra, Arnav; Chu, Yi; Mokadem, Mohamad; Nazzal, Lama
Enteric hyperoxaluria, a risk factor for kidney stone disease, often arises from malabsorptive bariatric surgeries or inflammatory bowel diseases. Current murine models for studying this condition are limited, necessitating new approaches. This study aims to establish two novel and distinct mouse models to investigate enteric hyperoxaluria: one simulating Roux-en-Y gastric bypass surgery and the other Crohn's ileitis. In the first model, diet-induced obese C57BL/6J male mice underwent either sham or bypass surgery, followed by three weeks on a high-fat, oxalate-enriched diet. In the second model, SAMP1/YitFc and AKR mice were gradually introduced to high-fat diets, later supplemented with oxalate while reducing fat content. Samples of urine, blood, and feces were collected to assess oxalate, creatinine, and fecal lipid profiles. Results showed hyperoxaluria and increased stool fat content, indicating fat malabsorption, in both SAMP1 and bypass mice compared to controls. Kidney injury was also observed. These findings confirm the successful establishment of enteric hyperoxaluria in both models, highlighting the role of dietary oxalate, intestinal inflammation, and fat malabsorption in disease progression. These models provide valuable tools for exploring cellular and molecular mechanisms in enteric hyperoxaluria and may inform future therapeutic strategies.
PMID: 40235154
ISSN: 1522-1547
CID: 5827912
Prdm16-dependent antigen-presenting cells induce tolerance to gut antigens
Fu, Liuhui; Upadhyay, Rabi; Pokrovskii, Maria; Chen, Francis M; Romero-Meza, Gabriela; Griesemer, Adam; Littman, Dan R
The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1-4. While RORγt+ antigen-presenting cells (RORγt-APCs) were shown to program gut microbiota-specific pTreg5-7, their definition remains incomplete, and the APC responsible for food tolerance has remained elusive. Here, we identify an APC subset required for differentiation of both food- and microbiota-specific pTreg cells and for establishment of oral tolerance. Development and function of these APCs require expression of the transcription factors Prdm16 and RORγt, as well as a unique Rorc(t) cis-regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish the pTreg-inducing APCs as myeloid in origin, distinct from ILC3, and sharing epigenetic profiles with classical dendritic cells (cDC), and designate them Prdm16+ RORγt+ tolerizing DC (tolDC). Upon genetic perturbation of tolDC, we observe a substantial increase in food antigen-specific T helper 2 (Th2) cells in lieu of pTreg, leading to compromised tolerance in mouse models of asthma and food allergy. Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tolDC with co-expression of PRDM16 and RORC and an extensive transcriptome shared with mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDC develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.
PMID: 40228524
ISSN: 1476-4687
CID: 5827502