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Browsing by Author "Langefeld, Carl"
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Item Geographic Disparities in Case Fatality and Discharge Disposition Among Patients With Primary Intracerebral Hemorrhage(American Heart Association, 2023) Bako, Abdulaziz T.; Potter, Thomas; Pan, Alan; Tannous, Jonika; Rahman, Omar; Langefeld, Carl; Woo, Daniel; Britz, Gavin; Vahidy, Farhaan S.; Medicine, School of MedicineBackground: We evaluate nationwide trends and urban–rural disparities in case fatality (in‐hospital mortality) and discharge dispositions among patients with primary intracerebral hemorrhage (ICH). Methods and Results: In this repeated cross‐sectional study, we identified adult patients (≥18 years of age) with primary ICH from the National Inpatient Sample (2004–2018). Using a series of survey design Poisson regression models, with hospital location–time interaction, we report the adjusted risk ratio (aRR), 95% CI, and average marginal effect (AME) for factors associated with ICH case fatality and discharge dispositions. We performed a stratified analysis of each model among patients with extreme loss of function and minor to major loss of function. We identified 908 557 primary ICH hospitalizations (overall mean age [SD], 69.0 [15.0] years; 445 301 [49.0%] women; 49 884 [5.5%] rural ICH hospitalizations). The crude ICH case fatality rate was 25.3% (urban hospitals: 24.9%, rural hospitals:32.5%). Urban (versus rural) hospital patients had a lower likelihood of ICH case fatality (aRR, 0.86 [95% CI, 0.83–0.89]). ICH case fatality is declining over time; however, it is declining faster in urban hospitals (AME, −0.049 [95% CI, −0.051 to −0.047]) compared with rural hospitals (AME, −0.034 [95% CI, −0.040 to −0.027]). Conversely, home discharge is increasing significantly among urban hospitals (AME, 0.011 [95% CI, 0.008–0.014]) but not significantly changing in rural hospitals (AME, −0.001 [95% CI, −0.010 to 0.007]). Among patients with extreme loss of function, hospital location was not significantly associated with ICH case fatality or home discharge. Conclusions: Improving access to neurocritical care resources, particularly in resource‐limited communities, may reduce the ICH outcomes disparity gap.Item The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair(Oxford University Press, 2019-04-08) Salvador Moreno, Naike; Liu, Jing; Haas, Karen M.; Parker, Laurie L.; Chakraborty, Chaitali; Kron, Stephen J.; Hodges, Kurt; Miller, Lance D.; Langefeld, Carl; Robinson, Paul J.; Lelièvre, Sophie A.; Vidi, Pierre-Alexandre; Physics, School of ScienceP53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.Item PRIORITIZATION OF RESULTS FROM WHOLE EXOME SEQUENCING IN FAMILIAL INTRACRANIAL ANEURYSM(Office of the Vice Chancellor for Research, 2012-04-13) Farlow, Janice L.; Lin, Hai; Hetrick, Kurt; Ling, Hua; Lai, Dongbing; Sauerbeck, Laura; Woo, Daniel; Langefeld, Carl; Brown, Robert; Pugh, Elizabeth; Doheny, Kimberly; Liu, Yunlong; Foroud, Tatiana; Broderick, Joseph; Foroud, TatianaWhole exome sequencing (WES) is an innovative approach to identifying rare variants associated with disease; however, reducing the large number of variants to a useful set of candidate genes is challenging. We developed a ranking system utilizing data from a previous genome-wide linkage analysis and various bioinformatics databases to prioritize the results of WES from families having multiple members with intracranial aneurysms. WES was performed in 35 affected individuals and 10 unaffected individ-uals across 7 families. All samples were genotyped (Illumina® OmniExpress) and sequenced (Agilent© SureSelect™ 50Mb Human All Exon Kit). Linkage analysis (Illumina 6K) was previously performed using autosomal domi-nant/recessive modes of inheritance. Application of quality filters resulted in 91,659 single nucleotide variants (SNVs). Nonsynonymous SNVs within an exon having an allele frequency of <3% were retained. Further filtering was performed based on Mendelian in-heritance (autosomal dominant or recessive). A ranking system prioritized retained variants based on the inheritance pattern specific to each family, occurrence in multiple families, relation to pathways and genes of interest, degree of penetrance, presence within a linkage peak, and whether the re-sultant proteins were predicted to be deleterious. Out of a 9-point score, 292 variants in 190 genes received scores of at least 5. Of these, 14 variants in 10 genes met the majority of prioritization criteria by achieving scores of over 7. While several WES studies have been successful at identifying genes im-portant to rare diseases, few have examined how to produce a list of candi-date genes contributing to a complex disease from WES data. We show that a ranking system that combines WES with bioinformatics resources and link-age data is a powerful approach to prioritize candidate genes for a complex disease like familial intracranial aneurysms. Subsequent studies are required to validate the utility of this approach.