Publications by authors named "Sehee Kim"

56 Publications

Association of Neighborhood Socioeconomic Status With Outcomes in Patients Surviving Stroke.

Neurology 2021 May 28;96(21):e2599-e2610. Epub 2021 Apr 28.

From the Department of Neurology (E.L.S.), University of Utah School of Medicine, Salt Lake City; and Departments of Epidemiology (E.L.S., E.T., C.-W.H., P.C., L.B.M., L.D.L.) and Biostatistics (S.K., Y.X.), School of Public Health, School of Kinesiology (E.T.), Institute for Social Research (P.C.), and Department of Neurology (L.B.M., L.D.L.), Michigan Medicine, University of Michigan, Ann Arbor.

Objective: To examine associations between neighborhood socioeconomic status (nSES) and 90-day poststroke outcomes.

Methods: The Brain Attack Surveillance in Corpus Christi Project is a population-based surveillance study in Nueces County, Texas. Patients with strokes were identified between 2010 and 2016 via active and passive surveillance and enrolled in the study. nSES index is a standardized composite of 2010 Census tract-level income, wealth, education, and employment (median -4.56, interquartile range -7.48 to -0.46). The 90-day outcomes were ascertained via interview: functional status measured by the average of 22 activities of daily living/instrumental activities of daily living (range 1-4), biopsychosocial health by the Stroke-Specific Quality of Life scale (range 0-5), and depressive symptoms by the 8-item Patient Health Questionnaire (range 0-24). Associations between nSES and outcomes were estimated using confounder-adjusted generalized estimating equations with an nSES × NIH Stroke Scale score interaction term.

Results: Seven hundred seventy-six survivors made up the analytical sample (52.96% male, 62.24% Mexican American, 52.96% ≥64 years old). Higher compared to lower nSES (mean difference comparing 75th to 25th percentile of nSES) was associated with better function (-0.27, 95% confidence interval [CI] -0.49 to -0.05), better biopsychosocial health (0.26, 95% CI 0.06-0.47), and fewer depressive symptoms (-1.77, 95% CI -3.306 to -0.48) among those with moderate to severe strokes. Among those with minor strokes, higher nSES was associated with better function (-0.13, 95% CI -0.24 to -0.02).

Conclusions: nSES may influence poststroke recovery. Studies should identify neighborhood characteristics that contribute to poststroke outcomes, particularly in moderate to severe stroke survivors.
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http://dx.doi.org/10.1212/WNL.0000000000011988DOI Listing
May 2021

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

Ann Neurol 2021 05 22;89(5):926-941. Epub 2021 Mar 22.

Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.

Objective: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRAS mutation induces sporadic bAVMs in mice.

Methods: Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRAS . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRAS -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor.

Results: The viral-mediated KRAS overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment.

Interpretation: Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.
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http://dx.doi.org/10.1002/ana.26059DOI Listing
May 2021

Amyotrophic Lateral Sclerosis Survival Associates With Neutrophils in a Sex-specific Manner.

Neurol Neuroimmunol Neuroinflamm 2021 03 2;8(2). Epub 2021 Feb 2.

From the Department of Neurology (B.J.M., S.A.G., E.L.F.), and Department of Biostatistics (J.B., S.K.), School of Public Health, University of Michigan, Ann Arbor.

Objective: To determine whether neutrophils contribute to amyotrophic lateral sclerosis (ALS) progression, we tested the association of baseline neutrophil count on ALS survival, whether the effect was sex specific, and whether neutrophils accumulate in the spinal cord.

Methods: A prospective cohort study was conducted between June 22, 2011, and October 30, 2019. Blood leukocytes were isolated from ALS participants and neutrophil levels assessed by flow cytometry. Participant survival outcomes were analyzed by groups (<2 × 10, 2-4 × 10, and >4 × 10 neutrophils/mL) with adjustments for relevant ALS covariates and by sex. Neutrophil levels were assessed from CNS tissue from a subset of participants.

Results: A total of 269 participants with ALS within 2 years of an ALS diagnosis were included. Participants with baseline neutrophil counts over 4 × 10/mL had a 2.1 times higher mortality rate than those with a neutrophil count lower than 2 × 10/mL (95% CI: 1.3-3.5, = 0.004) when adjusting for age, sex, and other covariates. This effect was more pronounced in females, with a hazard ratio of 3.8 (95% CI: 1.8-8.2, = 0.001) in the >4 × 10/mL vs <2 × 10/mL group. Furthermore, ALS participants (n = 8) had increased neutrophils in cervical ( = 0.049) and thoracic ( = 0.022) spinal cord segments compared with control participants (n = 8).

Conclusions: Higher neutrophil counts early in ALS associate with a shorter survival in female participants. Furthermore, neutrophils accumulate in ALS spinal cord supporting a pathophysiologic correlate. These data justify the consideration of immunity and sex for personalized therapeutic development in ALS.

Classification Of Evidence: This study provides Class III evidence that in female participants with ALS, higher baseline neutrophil counts are associated with shorter survival.
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http://dx.doi.org/10.1212/NXI.0000000000000953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057067PMC
March 2021

Advance Care Planning and Transitions to Comfort Measures after Stroke.

J Palliat Med 2020 Dec 23. Epub 2020 Dec 23.

Stroke Program, University of Michigan, Ann Arbor, Michigan, USA.

Advance care planning (ACP) is recommended to align treatment with patient goals, although there has been little study of the impact of ACP on in-hospital stroke treatment. To examine the association between ACP and transitions to comfort measures after stroke. Prospective cohort study. Hospitalized stroke patients 45 years and older and surrogate decision makers from a population-based study in Corpus Christi, TX. Surrogates were interviewed to assess presence of patient prestroke ACP, categorized as none, informal conversations only, or formal documentation. Patient records were reviewed for time from admission to transition to comfort measures only (CMO) (defined as in-hospital comfort measures or discharge with hospice services). Cox proportional-hazards models assessed the relationship between ACP and time to transition to CMO. Of 148 included stroke patients, 37% transitioned to CMO (median time five days). For ACP, 44% had only informal conversations, 38% had formal documentation (98% of which also reported informal conversations), and 18% had neither. After adjustment for age, severity, and baseline disability, informal conversations alone (hazard ratio [HR] 3.55; 95% confidence interval [CI]: 1.35-9.33) and formal documentation (HR 2.85; 95% CI: 1.05-7.72) were associated with earlier transition to comfort measures compared to no ACP. There was no difference between formal documentation and informal conversations on time to comfort measures (HR 0.80, 95% CI: 0.40-1.63). There was no additional association of formal ACP documentation over informal conversations on time to transition to comfort measures after stroke. Further study of formal ACP is warranted.
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http://dx.doi.org/10.1089/jpm.2020.0587DOI Listing
December 2020

Corrigendum to 'Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy' [Brain Dev. 42(6) (2020) 438-448].

Brain Dev 2021 Jan 29;43(1):179. Epub 2020 Sep 29.

Divison of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.braindev.2020.09.006DOI Listing
January 2021

Central sleep apnea is uncommon after stroke.

Sleep Med 2021 01 28;77:304-306. Epub 2020 Aug 28.

Stroke Program - Cardiovascular Center, Department of Neurology, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

Objective/background: Stroke is often considered a risk factor for central sleep apnea (CSA). The goal of this study was to determine the prevalence and clinical correlates of CSA in patients with ischemic stroke.

Patients/methods: In this analysis, 1346 participants in the Brain Attack Surveillance in Corpus Christi (BASIC) project underwent a home sleep apnea test shortly after ischemic stroke. Respiratory events during sleep were classified as central apneas, obstructive apneas, or hypopneas. Central apnea index (CAI) was defined as number of central apneas divided by recording time. CSA was defined as CAI ≥5/hour with at least 50% of all scored respiratory events classified as central apneas. Demographics and co-morbidities were ascertained from the medical record.

Results: Median CAI was 0/hour. Nineteen participants (1.4%) met criteria for CSA. Participants with CSA were more likely to be male, and had lower prevalence of obesity than participants without CSA. There was no association between CSA and other co-morbidities.

Conclusions: CSA was uncommon in this large cohort of patients with recent ischemic stroke.
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http://dx.doi.org/10.1016/j.sleep.2020.08.025DOI Listing
January 2021

Untargeted metabolomics yields insight into ALS disease mechanisms.

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1329-1338. Epub 2020 Sep 14.

Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA

Objective: To identify dysregulated metabolic pathways in amyotrophic lateral sclerosis (ALS) versus control participants through untargeted metabolomics.

Methods: Untargeted metabolomics was performed on plasma from ALS participants (n=125) around 6.8 months after diagnosis and healthy controls (n=71). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon rank-sum tests, adjusted logistic regression and partial least squares-discriminant analysis (PLS-DA), while group lasso explored sub-pathway-level differences. Adjustment parameters included sex, age and body mass index (BMI). Metabolomics pathway enrichment analysis was performed on metabolites selected by the above methods. Finally, machine learning classification algorithms applied to group lasso-selected metabolites were evaluated for classifying case status.

Results: There were no group differences in sex, age and BMI. Significant metabolites selected were 303 by Wilcoxon, 300 by logistic regression, 295 by PLS-DA and 259 by group lasso, corresponding to 11, 13, 12 and 22 enriched sub-pathways, respectively. 'Benzoate metabolism', 'ceramides', 'creatine metabolism', 'fatty acid metabolism (acyl carnitine, polyunsaturated)' and 'hexosylceramides' sub-pathways were enriched by all methods, and 'sphingomyelins' by all but Wilcoxon, indicating these pathways significantly associate with ALS. Finally, machine learning prediction of ALS cases using group lasso-selected metabolites achieved the best performance by regularised logistic regression with elastic net regularisation, with an area under the curve of 0.98 and specificity of 83%.

Conclusion: In our analysis, ALS led to significant metabolic pathway alterations, which had correlations to known ALS pathomechanisms in the basic and clinical literature, and may represent important targets for future ALS therapeutics.
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http://dx.doi.org/10.1136/jnnp-2020-323611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677469PMC
December 2020

Mexican American Immigrants Demonstrate Better Functional Stroke Outcomes Compared With Mexican American Nonimmigrants.

Stroke 2020 10 1;51(10):3129-3132. Epub 2020 Sep 1.

University of Michigan Medical School, Ann Arbor (C.N.H., L.L., L.B.M.).

Background And Purpose: We analyzed differences in 90-day poststroke outcomes between Mexican Americans born in the United States (nonimmigrant) compared with those born outside the United States (immigrant).

Methods: We performed a retrospective analysis of prospective data from the population-based Brain Attack Surveillance in Corpus Christi project. We identified stroke cases from 2008 to 2016 and quantified functional, cognitive, and neurological outcomes. Associations between outcome scores and immigration status were analyzed using weighted linear regression models.

Results: Eighty-three Mexican American stroke cases (n=935) were immigrants, and 852 stroke cases were nonimmigrants. Average length of stay in the United States for immigrants was 47 years. Immigrants were older (69 versus 66 years), more likely men (60% versus 49%), had less education on average, and were more likely to have atrial fibrillation compared with nonimmigrants. No differences in other comorbidities existed between groups. After adjustment for confounders, immigrants had better functional outcomes (activities of daily living/instrumental activities of daily living; mean difference, -0.22; =0.02; 1-4, higher scores worse) and no difference in neurological outcomes (log-National Institutes of Health Stroke Scale; mean difference, -0.15; =0.15; 0-44, higher scores worse) or cognitive outcomes (3 Mini-Mental State Examination; mean difference, -0.79; =0.64; 0-100, lower scores worse).

Conclusions: Long-term Mexican American immigrants in this community display better stroke functional outcomes than nonimmigrant Mexican Americans and comparable neurological and cognitive outcomes.
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http://dx.doi.org/10.1161/STROKEAHA.120.030915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530126PMC
October 2020

Family Perceptions of Quality of End-of-Life Care in Stroke.

Palliat Med Rep 2020 23;1(1):129-134. Epub 2020 Jul 23.

Stroke Program, Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Most end-of-life decisions after stroke are made by a surrogate decision maker, yet there has been limited study of surrogate assessment of the quality of end-of-life stroke care. To assess surrogate perceptions of quality of end-of-life care (QEOLC) in stroke and explore factors associated with quality. Cross-sectional analysis of interviewer-administered survey. Surrogate decision makers for deceased stroke patients in a population-based study. The primary outcome was the validated 10-item family version of the QEOLC scale. The univariate association between prespecified patient and surrogate factors and dichotomized QEOLC score (high: 8-10, low: 0-7) was explored with logistic regression fit using generalized estimating equations. Seventy-nine surrogates for 66 deceased stroke cases were enrolled (median patient age: 76, female patient: 53%, Mexican American patient: 59%, median time from stroke to death: seven days, median surrogate age: 59, and female surrogate: 72%). The overall QEOLC was generally high (median 8.3, quartiles 6.1, 9.6) although several individual items had a high proportion (∼30%-50%) of surrogates who felt that the questions did not apply to the patient's situation. No hypothesized factors were associated with QEOLC score, including demographics, stroke type, location/timing of death, advance directives, health literacy, or understanding of patient wishes. Surrogates reported generally high QEOLC. Although this finding is encouraging, modifications to the QEOLC may be needed in stroke as some surrogates were unable to provide a valid response for certain items.
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http://dx.doi.org/10.1089/pmr.2020.0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446249PMC
July 2020

Prediction of sleep-disordered breathing after stroke.

Sleep Med 2020 11 15;75:1-6. Epub 2020 May 15.

Stroke Program, University of Michigan, United States; Department of Epidemiology, School of Public Health, University of Michigan, United States.

Objective/background: Sleep-disordered breathing (SDB) is highly prevalent after stroke and is associated with poor outcomes. Currently, after stroke, objective testing must be used to differentiate patients with and without SDB. Within a large, population-based study, we evaluated the usefulness of a flexible statistical model based on baseline characteristics to predict post-stroke SDB.

Patients/methods: Within a population-based study, participants (2010-2018) underwent SDB screening, shortly after ischemic stroke, with a home sleep apnea test. The respiratory event index (REI) was calculated as the number of apneas and hypopneas per hour of recording; values ≥10 defined SDB. The distributed random forest classifier (a machine learning technique) was applied to predict SDB with the following as predictors: demographics, stroke risk factors, stroke severity (NIHSS), neck and waist circumference, palate position, and pre-stroke symptoms of snoring, apneas, and sleepiness.

Results: Within the total sample (n = 1330), median age was 65 years; 47% were women; 32% non-Hispanic white, 62% Mexican American, and 6% African American. SDB was found in 891 (67%). The area under the receiver operating characteristic curve, a measure of predictive ability, applied to the validation sample was 0.75 for the random forest model. Random forest correctly classified 72.5% of validation samples.

Conclusions: In this large, ethnically diverse, population-based sample of ischemic stroke patients, prediction models based on baseline characteristics and clinical measures showed fair rather than clinically reliable performance, even with use of advanced machine learning techniques. Results suggest that objective tests are still needed to differentiate ischemic stroke patients with and without SDB.
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http://dx.doi.org/10.1016/j.sleep.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666648PMC
November 2020

Trends in Stroke Recurrence in Mexican Americans and Non-Hispanic Whites.

Stroke 2020 08 16;51(8):2428-2434. Epub 2020 Jul 16.

Stroke Program, University of Michigan Medical School (C.B.S., L.D.L., D.B.Z., D.L.B., L.E.S., J.F.B., K.A.K., W.J.M., L.B.M.).

Background And Purpose: Stroke incidence and mortality are declining rapidly in developed countries. Little data on ethnic-specific stroke recurrence trends exist. Fourteen-year stroke recurrence trend estimates were evaluated in Mexican Americans and non-Hispanic whites in a population-based study.

Methods: Recurrent stroke was ascertained prospectively in the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in Texas, between 2000 and 2013. Incident cases were followed forward to determine 1- and 2-year recurrence. Fine & Gray subdistribution hazard models were used to estimate adjusted trends in the absolute recurrence risk and ethnic differences in the secular trends. The ethnic difference in the secular trend was examined using an interaction term between index year and ethnicity in the models adjusted for age, sex, hypertension, diabetes mellitus, smoking, atrial fibrillation, insurance, and cholesterol and relevant interaction terms.

Results: From January 1, 2000 to December 31, 2013 (N=3571), the cumulative incidence of 1-year recurrence in Mexican Americans decreased from 9.26% (95% CI, 6.9%-12.43%) in 2000 to 3.42% (95% CI, 2.25%-5.21%) in 2013. Among non-Hispanic whites, the cumulative incidence of 1-year recurrence in non-Hispanic whites decreased from 5.67% (95% CI, 3.74%-8.62%) in 2000 to 3.59% (95% CI, 2.27%-5.68%) in 2013. The significant ethnic disparity in stroke recurrence existed in 2000 (risk difference, 3.59% [95% CI, 0.94%-6.22%]) but was no longer seen by 2013 (risk difference, -0.17% [95% CI, -1.96% to 1.5%]). The competing 1-year mortality risk was stable over time among Mexican Americans, while for non-Hispanic whites it was decreasing over time (difference between 2000 and 2013: -4.67% [95% CI, -8.72% to -0.75%]).

Conclusions: Mexican Americans had significant reductions in stroke recurrence despite a stable death rate, a promising indicator. The ethnic disparity in stroke recurrence present early in the study was gone by 2013.
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http://dx.doi.org/10.1161/STROKEAHA.120.029376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387185PMC
August 2020

A Fast and Accurate Method for Genome-Wide Time-to-Event Data Analysis and Its Application to UK Biobank.

Am J Hum Genet 2020 08 25;107(2):222-233. Epub 2020 Jun 25.

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Graduate School of Data Science, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

With increasing biobanking efforts connecting electronic health records and national registries to germline genetics, the time-to-event data analysis has attracted increasing attention in the genetics studies of human diseases. In time-to-event data analysis, the Cox proportional hazards (PH) regression model is one of the most used approaches. However, existing methods and tools are not scalable when analyzing a large biobank with hundreds of thousands of samples and endpoints, and they are not accurate when testing low-frequency and rare variants. Here, we propose a scalable and accurate method, SPACox (a saddlepoint approximation implementation based on the Cox PH regression model), that is applicable for genome-wide scale time-to-event data analysis. SPACox requires fitting a Cox PH regression model only once across the genome-wide analysis and then uses a saddlepoint approximation (SPA) to calibrate the test statistics. Simulation studies show that SPACox is 76-252 times faster than other existing alternatives, such as gwasurvivr, 185-511 times faster than the standard Wald test, and more than 6,000 times faster than the Firth correction and can control type I error rates at the genome-wide significance level regardless of minor allele frequencies. Through the analysis of UK Biobank inpatient data of 282,871 white British European ancestry samples, we show that SPACox can efficiently analyze large sample sizes and accurately control type I error rates. We identified 611 loci associated with time-to-event phenotypes of 12 common diseases, of which 38 loci would be missed within a logistic regression framework with a binary phenotype defined as event occurrence status during the follow-up period.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413891PMC
August 2020

Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy.

Brain Dev 2020 Jun 2;42(6):438-448. Epub 2020 Mar 2.

Divison of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul, South Korea. Electronic address:

Background: Early-onset developmental and epileptic encephalopathy (DEE) is characterized by repeated seizures beginning within 3 months of birth and severe interictal epileptiform discharge, including burst suppression. This study assessed the utility of targeted gene panel sequencing in the genetic diagnosis of this disease.

Materials And Methods: Targeted gene panel sequencing was performed in 150 early infantile-onset DEE patients (≤3 months of age), and we extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype.

Results: Of the early infantile-onset DEE patients, 70 were neonatal-onset DEE and the other 80 patients began experiencing seizures from 1 to 3 months after birth. There were 11 different pathogenic or likely pathogenic variants among 34.7% (52/150) of patients with early infantile-onset DEE, in whom KCNQ2, STXBP1, CDKL5, and SCN1A were the major pathogenic variants. Among the neonatal-onset DEE patients, pathological genes were identified in 42.9% (30/70), indicating a significantly higher diagnostic yield than in 27.5% (22/80) of patients who experienced seizure onset 1 to 3 months after birth (p = 0.048). Among the neonatal-onset DEE group, variants in KCNQ2, STXBP1, and CDKL5 were detected at high frequencies, accounting for 66.7% (20/30) of the pathogenic or likely pathogenic variants found in this study.

Conclusion: Targeted gene panel sequencing demonstrated a high yield of pathogenic variants in the diagnosis of early-onset epileptic encephalopathy, especially in those with neonatal-onset DEE. Early diagnosis of early-onset epileptic encephalopathy may improve the prognosis of patients by earlier selection of appropriate treatment based on pathogenic variant.
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http://dx.doi.org/10.1016/j.braindev.2020.02.004DOI Listing
June 2020

Arteriovenous Fistula Use in the United States and Dialysis Facility-Level Comorbidity Burden.

Am J Kidney Dis 2020 06 22;75(6):879-886. Epub 2019 Nov 22.

Division of Nephrology, University of Michigan Health System, Ann Arbor, MI.

Rationale & Objective: Patients with multiple comorbid conditions are less likely to use an arteriovenous fistula (AVF) for hemodialysis vascular access. Some dialysis facilities have high rates of AVF placement despite having patients with many comorbid conditions. This study describes variation in facility-level use of AVFs across the facility-level burden of patient comorbid conditions.

Study Design: Retrospective cohort study.

Setting & Participants: Medicare patients receiving hemodialysis for 1 year or more in US dialysis facilities.

Predictors: Facility-level burden of patient comorbid conditions; patient characteristics.

Outcomes: Odds of AVFs versus other access types; facility-level use of AVFs.

Analytical Approach: Facility-level comorbidity burden was calculated by summing individual comorbid conditions, determining the average per patient, then defining 11 groups based on facility percentile ranking. Generalized estimating equations with a logit link were used to estimate the odds of AVF placement at the patient level. For the facility-level analysis, a generalized estimating equation model with the identity link was fit to characterize the percentage of AVF use at each facility.

Results: Overall, AVF use was 65.8% in 315,919 prevalent hemodialysis patients among 5,813 facilities. After adjustment for patient characteristics, AVF use was 0.27, 0.30, 1.05, and 1.74 percentage points lower than the median among facilities in the 61st to 70th, 71st to 80th, 81st to 90th, and 91st to 99th percentiles of comorbidity, respectively, and 0.42, 0.63, 1.34, and 1.90 percentage points higher than the median among facilities in the 31st to 40th, 21st to 30th, 11th to 20th, and 1st to 10th percentiles of comorbidity, respectively. Facilities in the greater than 99th percentile of comorbidity burden had AVF use that was 3.47 percentage points lower than the median. Facilities in the less than 1st percentile of comorbidity burden had AVF use that was 2.64 percentage points greater than the median.

Limitations: Limited to Medicare dialysis-dependent patients treated for 1 year or more.

Conclusions: After adjustment for patient characteristics, we found small differences in facility rates of AVF use except in the extremes of high or low levels of comorbidity burden. Our study demonstrates that dialysis facilities with a relatively high patient comorbidity burden can achieve similar fistula rates as facilities with healthier patients. Although high comorbidity burden does not explain low facility AVF use, additional study is needed to understand differences in AVF use rates between facilities with similar comorbidity burdens.
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http://dx.doi.org/10.1053/j.ajkd.2019.08.023DOI Listing
June 2020

Do apneas and hypopneas best reflect risk for poor outcomes after stroke?

Sleep Med 2019 11 27;63:14-17. Epub 2019 May 27.

Stroke Program, University of Michigan Medical School, USA; Department of Epidemiology, School of Public Health, University of Michigan, USA.

Objective/background: Sleep apnea (SA) is associated with poor outcomes after stroke. The best sleep apnea-related measure to capture this relationship is currently unknown. This measure or its underlying pathophysiology could serve as a treatment target.

Patients/methods: Within the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project, the ApneaLink Plus was used to perform sleep apnea tests shortly after ischemic stroke (2010-2015). Functional and cognitive outcomes were measured via in-person interviews 90-days post-stroke. Recurrent stroke was assessed longitudinally through active and passive surveillance procedures. After standardization to allow direct comparisons, adjusted models were built for each ApneaLink Plus measure and each outcome, to assess the effect of 1 standard deviation difference in the measure.

Results: Among 995 subjects, median age was 67 years (interquartile range: 59, 78) and 52% were women. The respiratory event index had the strongest relationship with functional outcome (mean difference = 0.094, 95% confidence interval (CI): 0.040, 0.147). Desaturations ≤85% were associated with worse functional outcome (mean difference = 0.016, 95% CI: 0.002, 0.030), but desaturations ≤ 90% were not. Obstructive apnea index (OAI) showed the strongest association with cognitive outcome (mean difference = -0.079, 95% CI: -0.162, 0.005), but was not significant. Oxygen desaturation index (ODI) showed the strongest association with recurrent ischemic stroke (hazard ratio = 1.338, 95% CI: 1.016, 1.759).

Conclusions: Measurements easily obtained from a commonly used home sleep apnea test predicted outcomes differentially. This suggests the possibility of different SA-associated targets (perhaps using strategies more tolerable than standard treatment) based on the outcome of interest.
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http://dx.doi.org/10.1016/j.sleep.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939631PMC
November 2019

Associations of Self-Reported History of Depression and Antidepressant Use Before Stroke Onset With Poststroke Post-Acute Rehabilitation Care-An Exploratory Study: The BASIC (Brain Attack Surveillance in Corpus Christi) Project.

J Am Heart Assoc 2019 08 19;8(16):e013382. Epub 2019 Aug 19.

Department of Epidemiology University of Michigan School of Public Health Ann Arbor MI.

Background Prestroke depression status and post-acute rehabilitation care (PARC) are determinants of poststroke depression and function. However, little is known on how prestroke depression status affects PARC placement, a possible pathway for upstream intervention. We examined how prestroke depression status affects PARC in a population-based study. Methods and Results Incident ischemic stroke cases were from the BASIC (Brain Attack Surveillance in Corpus Christi) Project from 2008 to 2012. Prestroke depression status was self-reported and categorized as (1) never depressed, (2) history of depression without antidepressant use before stroke onset, or (3) antidepressant use before stroke onset. PARC included home, a skilled nursing facility, or an inpatient rehabilitation facility. Confounder-adjusted multinomial regression models were used to examine the association between prestroke depression status and PARC. Adjustment for stroke severity was deferred in the main analyses because it may lie on the causal pathway. There were 548 stroke survivors (mean age 65.3 years, 48.3% female, 62.6% Mexican-American). The adjusted odds ratios comparing home discharge to a skilled nursing facility were 1.88 (95% CI: 0.86-4.11) for those with a history of depression and 2.55 (95% CI: 1.11-5.83) for those using an antidepressant at stroke onset, relative to those never depressed. The adjusted odds ratios comparing an inpatient rehabilitation facility to a skilled nursing facility were 1.17 (95% CI 0.40-3.42) and 3.28 (95% CI 1.24-8.67) for those with a history of depression and those using an antidepressant at stroke onset, respectively, relative to those never depressed. Conclusions Antidepressant use before stroke onset may increase odds of home and inpatient rehabilitation facility discharge compared with skilled nursing facility discharge.
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http://dx.doi.org/10.1161/JAHA.119.013382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759886PMC
August 2019

Safety and Effectiveness of Contemporary P2Y Inhibitors in an East Asian Population With Acute Coronary Syndrome: A Nationwide Population-Based Cohort Study.

J Am Heart Assoc 2019 07 16;8(14):e012078. Epub 2019 Jul 16.

Division of Cardiology Asan Medical Center University of Ulsan College of Medicine Seoul Republic of Korea.

Background Prior reports indicate that the effect of P2Y inhibitors may be different in East Asian patients ("East Asian paradox"); therefore, understanding the outcomes associated with potent P2Y inhibitors in different populations is clinically important. Methods and Results In this observational cohort study using administrative healthcare data sets, we compared safety and effectiveness of contemporary P2Y inhibitors in patients with acute coronary syndrome. The primary safety outcomes were major and any bleeding, and the primary effectiveness outcomes were major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) and all-cause mortality. Among 70 715 patients with acute coronary syndrome, 56 216 (79.5%) used clopidogrel, 11 402 (16.1%) used ticagrelor, and 3097 (4.4%) used prasugrel. The median follow-up period was 18.0 months (interquartile range: 9.6-26.4 months). In a propensity-matched cohort, compared with clopidogrel, ticagrelor was associated with a higher risk of any bleeding (hazard ratio: 1.23; 95% CI, 1.14-1.33) but a lower risk of mortality (hazard ratio: 0.76; 95% CI, 0.63-0.91). Prasugrel, compared with clopidogrel, was associated with higher risks of any bleeding (hazard ratio: 1.23; 95% CI, 1.06-1.43) and major bleeding (hazard ratio: 1.50; 95% CI, 1.01-2.21) but a similar risk of effectiveness outcomes. No significant difference was noted between ticagrelor and prasugrel with respect to key safety or effectiveness outcomes. Several sensitivity analyses showed similar results. Conclusions In East Asian patients with acute coronary syndrome, compared with clopidogrel, ticagrelor was associated with an increased risk of bleeding but a decreased risk of mortality. Prasugrel was associated with an increase of any bleeding without difference in effectiveness outcomes. The risks of bleeding and ischemic events were similar between ticagrelor and prasugrel.
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http://dx.doi.org/10.1161/JAHA.119.012078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662138PMC
July 2019

Estimating Outcome-Exposure Associations when Exposure Biomarker Detection Limits vary Across Batches.

Epidemiology 2019 09;30(5):746-755

From the Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.

Limit of detection (LOD) issues are ubiquitous in exposure assessment. Although there is an extensive literature on modeling exposure data under such imperfect measurement processes, including likelihood-based methods and multiple imputation, the standard practice continues to be naïve single imputation by a constant (e.g., (Equation is included in full-text article.)). In this article, we consider the situation where, due to the practical logistics of data accrual, sampling, and resource constraints, exposure data are analyzed in multiple batches where the LOD and the proportion of censored observations differ across batches. Compounding this problem is the potential for nonrandom assignment of samples to each batch, often driven by enrollment patterns and biosample storage. This issue is particularly important for binary outcome data where batches may have different levels of outcome enrichment. We first consider variants of existing methods to address varying LODs across multiple batches. We then propose a likelihood-based multiple imputation strategy to impute observations that are below the LOD while simultaneously accounting for differential batch assignment. Our simulation study shows that our proposed method has superior estimation properties (i.e., bias, coverage, statistical efficiency) compared to standard alternatives, provided that distributional assumptions are satisfied. Additionally, in most batch assignment configurations, complete-case analysis can be made unbiased by including batch indicator terms in the analysis model, although this strategy is less efficient relative to the proposed method. We illustrate our method by analyzing data from a cohort study in Puerto Rico that is investigating the relation between endocrine disruptor exposures and preterm birth.
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http://dx.doi.org/10.1097/EDE.0000000000001052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677587PMC
September 2019

Time Trends in Race-Ethnic Differences in Do-Not-Resuscitate Orders After Stroke.

Stroke 2019 07 10;50(7):1641-1647. Epub 2019 Jun 10.

Stroke Program (R.J.L., E.C., N.M.G., L.D.L., L.B.M., D.B.Z.), Michigan Medicine, Ann Arbor.

Background and Purpose- Do-not-resuscitate (DNR) orders are common after stroke, though there are limited data on trends over time. We investigated time trends in DNR orders in a community with a large minority population. Methods- Cases of ischemic stroke (IS) or intracerebral hemorrhage (ICH) were identified from the BASIC study (Brain Attack Surveillance in Corpus Christi) from June 2007 through October 2016. Cox proportional hazards models were used to assess time to DNR orders, with an interaction term added to allow separate hazard ratios for early (≤24 hours) and late (>24 hours) DNR. Stroke type-specific calendar trends were assessed with an interaction term between calendar year (linear) and stroke type. Results- Two thousand six hundred seventy-two cases were included (ICH, 14%). Mean age was 69, 50% were female, and race-ethnicity was Mexican American (58%), non-Hispanic white (37%), and African American (5%). Overall, 16% had a DNR order during the hospitalization. For ICH, DNR orders (early and late) were stable over the study period. However, early DNR orders became more common over time after ischemic stroke (hazard ratio for 2016 versus 2007: 1.89; 95% CI, 1.06-3.39), with no change over time for late DNR orders after ischemic stroke. Mexican Americans (hazard ratio, 0.65; 95% CI, 0.50-0.86) and African Americans (hazard ratio, 0.17; 95% CI, 0.04-0.71) were less likely than non-Hispanic whites to have early DNR orders, though there were no race-ethnic differences in late DNR orders. There was no change in race-ethnic difference in DNR orders over the time of the study (interaction P>0.60). Conclusions- Despite revised national guidelines cautioning against early DNR orders in ICH, presence of DNR orders after ICH was stable between 2007 and 2016, with only slight increases in early DNR orders after ischemic stroke. Mexican Americans and African Americans remain less likely than non-Hispanic whites to have early DNR orders after stroke.
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http://dx.doi.org/10.1161/STROKEAHA.118.024460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597008PMC
July 2019

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy.

Hepatol Commun 2019 May 25;3(5):685-696. Epub 2019 Mar 25.

Children's Hospital Colorado, University of Colorado School of Medicine Aurora CO.

Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T- and B-cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen-DR isotype [HLA-DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA-DRCD38 NK cells and expression of NK cell activation markers CD69 and HLA-DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)-8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA-DRCD38 NK cells and plasma IL-8 levels was associated with an increased risk of transplant or death by day 360. Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL-8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.
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http://dx.doi.org/10.1002/hep4.1332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492477PMC
May 2019

Comparative effectiveness analysis of Medicare dialysis facility survey processes.

PLoS One 2019 26;14(4):e0216038. Epub 2019 Apr 26.

Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, Michigan, United States of America.

Background: To assure and improve the quality and safety of care provided by dialysis facilities, federal oversight has been conducted through periodic survey assessment. However, with the growing number of individuals living with ESRD and dialysis facilities, state survey agencies have faced challenges in time and resources to complete survey activities. Therefore, the survey process ('Basic Survey' used prior to 2013) was redesigned in order to develop a more efficient process ('Core Survey' newly implemented since 2013). The purpose of this analysis was to evaluate and compare dialysis facility survey outcomes between the Core and Basic Survey processes, using a causal inference technique. The survey outcomes included condition-level citations, total citations (condition- and standard-level), and citation rate per survey-hour.

Methods: For comparisons of non-randomly assigned survey types, propensity score matching was used. Data were drawn from CMS' Quality Improvement Evaluation System (QIES) database from January 1, 2013 through July 31, 2014. Covariates available included survey type, facility characteristics (state, urban, practices catheter reuse, dialysis modalities offered, number of patients, mortality, hospitalization, infection) and survey-related characteristics (number of surveyors, time since last survey).

Results: Compared to the Basic Survey, the Core Survey identified 10% more total citations (P = 0.001) and identified condition-level citations more frequently, although the latter finding did not reach statistical significance. These findings suggest an increase of 10% in citation rate (i.e. ratio between citations and survey time) with the Core survey process (P = 0.002).

Conclusions: Greater efficiency has implications for attenuating the time-intensive burden of the state survey process, and improving the safety and quality of care provided by dialysis facilities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216038PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485704PMC
January 2020

Inter-Unit Reliability for Quality Measure Testing.

J Hosp Adm 2019 Apr 8;8(2):1-6. Epub 2019 Jan 8.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, United States.

Facility-specific quality measures are commonly used to monitor dialysis facilities. To successfully develop, test and validate quality measures, a subset of facilities are often recruited for preliminary evaluations. To ensure that the facility-specific measures will achieve a desirable precision, it is often of interest to determine a minimum number of facilities that should be recruited. To achieve this, we propose a method based on the inter-unit reliability (IUR), which is commonly used to assess quality measures. In particular, the confidence intervals of the IUR are calculated, with the width of this confidence interval measuring the precision of the estimate of the IUR. To assess the performance of the estimated IUR with various numbers of facilities, a simulation study is conducted. The IURs are then computed to develop and implement a quality measure that is used to guard against high ultrafiltration rates for adult dialysis patient with End-Stage Renal Disease. The estimated values are helpful to determine a minimum number of facilities that should be recruited in the measure testing process.
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http://dx.doi.org/10.5430/jha.v8n2p1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455941PMC
April 2019

Sinking Skin Flap Syndrome or Syndrome of the Trephined: A Report of Two Cases.

Ann Rehabil Med 2019 Feb 28;43(1):111-114. Epub 2019 Feb 28.

Department of Rehabilitation Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Decompressive craniectomy (DC) is commonly performed in patients with intracranial hypertension or brain edema due to traumatic brain injury. Infrequently, neurologic deteriorations accompanied by sunken scalp may occur after DC. We report two patients with traumatic subdural hemorrhage who had neurologic deteriorations accompanied by sunken scalp after DC. Neurologic function improved dramatically in both patients after cranioplasty. Monitoring for neurologic deterioration after craniectomy is advised. For patients showing neurologic deficit with a sunken scalp, early cranioplasty should be considered.
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http://dx.doi.org/10.5535/arm.2019.43.1.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409664PMC
February 2019

Sleep-Disordered Breathing Is Associated With Recurrent Ischemic Stroke.

Stroke 2019 03;50(3):571-576

From the Stroke Program (D.L.B., E.C., L.B.M., L.D.L.), University of Michigan Medical School, University of Michigan, Ann Arbor.

Background and Purpose- Limited data are available about the relationship between sleep-disordered breathing (SDB) and recurrent stroke and mortality, especially from population-based studies, large samples, or ethnically diverse populations. Methods- In the BASIC project (Brain Attack Surveillance in Corpus Christ), we identified patients with ischemic stroke (2010-2015). Subjects were offered screening for SDB with the ApneaLink Plus device, from which a respiratory event index (REI) score ≥10 defined SDB. Demographics and baseline characteristics were determined from chart review and interview. Recurrent ischemic stroke was identified through active and passive surveillance. Cause-specific proportional hazards models were used to assess the association between REI (modeled linearly) and ischemic stroke recurrence (as the event of interest), and all-cause poststroke mortality, adjusted for multiple potential confounders. Results- Among 842 subjects, the median age was 65 (interquartile range, 57-76), 47% were female, and 58% were Mexican American. The median REI score was 14 (interquartile range, 6-26); 63% had SDB. SDB was associated with male sex, Mexican American ethnicity, being insured, nonsmoking status, diabetes mellitus, hypertension, lower educational attainment, and higher body mass index. Among Mexican American and non-Hispanic whites, 85 (11%) ischemic recurrent strokes and 104 (13%) deaths occurred, with a median follow-up time of 591 days. In fully adjusted models, REI was associated with recurrent ischemic stroke (hazard ratio, 1.02 [hazard ratio for one-unit higher REI score, 95% CI, 1.01-1.03]), but not with mortality alone (hazard ratio, 1.00 [95% CI, 0.99-1.02]). Conclusions- Results from this large population-based study show that SDB is associated with recurrent ischemic stroke, but not mortality. SDB may therefore represent an important modifiable risk factor for poor stroke outcomes.
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http://dx.doi.org/10.1161/STROKEAHA.118.023807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389387PMC
March 2019

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

Int J Cancer 2019 05 20;144(9):2192-2205. Epub 2019 Jan 20.

Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.
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http://dx.doi.org/10.1002/ijc.32029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399057PMC
May 2019

Effect of nocturnal hemodialysis on sleep parameters in patients with end-stage renal disease: a systematic review and meta-analysis.

PLoS One 2018 11;13(9):e0203710. Epub 2018 Sep 11.

Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China.

Introduction: Recently, a small but growing literature has depicted the beneficial effects of nocturnal hemodialysis (NHD) over conventional hemodialysis (CHD) in the fields of sleep disorders such as sleep apnea. The impact of various dialysis models on sleep disorders, however, has not been determined. The objective of our meta-analysis is to examine the potential effects of NHD, compared with CHD, on sleep disorders in HD patients.

Methods: Several electronic databases including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and CNKI were searched, using the search terms "nocturnal" (or "nightly") and "dialysis" (or "hemodialysis" or "renal dialysis") from the earliest available date of indexing to March 2018. Two authors independently extracted data, evaluated the study quality, and conducted random-effects meta-analyses using STATA 12.0.

Results: Of 1789 potentially relevant citations, 9 fulfilled eligibility criteria, consisting of 6 single-arm studies (comparing pre- and post-intervention outcomes), 1 observational study, and 2 randomized controlled trials (a total of 286 participants). Regarding objective sleep assessments, conversion from CHD to NHD resulted in a significant reduction in the AHI (Mean difference was -14.90; 95% CI, -20.12 to -9.68), a significant increase of SaO2 (Mean difference was 1.38%; 95% CI, 0.35% to 2.42%), and a significant decrease of TST (Mean difference was -0.31; 95% CI, -0.47 to -0.15). The trends were even stronger in the HD patients with sleep disorders. However, regarding subjective sleep assessments, improved sleep quality was found in the prospective pre-post intervention studies and cohort studies, while no significant improvements were found in the randomized controlled trials.

Conclusion: Although a significant improvement of sleep apnea was observed by switching from CHD to NHD, it may not yield a net benefit in overall subjective sleep quality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203710PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133364PMC
February 2019

Redox-Responsive Manganese Dioxide Nanoparticles for Enhanced MR Imaging and Radiotherapy of Lung Cancer.

Front Chem 2017 4;5:109. Epub 2017 Dec 4.

Biomarker Branch, National Cancer Center, Goyang, South Korea.

In this study, we synthesized manganese dioxide nanoparticles (MnO NPs) stabilized with biocompatible polymers (polyvinylpyrrolidone and polyacrylic acid) and analyzed their effect on non-small cell lung cancer (NSCLC) cells with or without gefitinib resistance . MnO NPs showed glutathione (GSH)-responsive dissolution and subsequent enhancement in magnetic resonance (MR) imaging. Of note, treatment with MnO NPs induced significant cytotoxic effects on NSCLC cells, and additional dose-dependent therapeutic effects were obtained upon X-ray irradiation. Normal cells treated with MnO NPs were viable at the tested concentrations. In addition, increased therapeutic efficacy could be achieved when the cells were treated with MnO NPs in hypoxic conditions. Therefore, we conclude that the use of MnO NPs in MR imaging and combination radiotherapy may be an efficient strategy for the imaging and therapy of NSCLC.
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http://dx.doi.org/10.3389/fchem.2017.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722798PMC
December 2017

Mdivi-1 Protects Adult Rat Hippocampal Neural Stem Cells against Palmitate-Induced Oxidative Stress and Apoptosis.

Int J Mol Sci 2017 Sep 11;18(9). Epub 2017 Sep 11.

Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 02447, Korea.

Palmitate concentrations in type 2 diabetic patients are higher than in healthy subjects. The prolonged elevation of plasma palmitate levels induces oxidative stress and mitochondrial dysfunction in neuronal cells. In this study, we examined the role of mdivi-1, a selective inhibitor of mitochondrial fission protein dynamin-regulated protein 1 (Drp1), on the survival of cultured hippocampal neural stem cells (NSCs) exposed to high palmitate. Treatment of hippocampal NSCs with mdivi-1 attenuated palmitate-induced increase in cell death and apoptosis. Palmitate exposure significantly increased Drp1 protein levels, which were prevented by pretreatment of cells with mdivi-1. We found that cytosolic Drp1 was translocated to the mitochondria when cells were exposed to palmitate. In contrast, palmitate-induced translocation of Drp1 was inhibited by mdivi-1 treatment. We also investigated mdivi-1 regulation of apoptosis at the mitochondrial level. Mdivi-1 rescued cells from palmitate-induced lipotoxicity by suppressing intracellular and mitochondrial reactive oxygen species production and stabilizing mitochondrial transmembrane potential. Mdivi-1-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Our data suggest that mdivi-1 protects hippocampal NSCs against lipotoxicity-associated oxidative stress by preserving mitochondrial integrity and inhibiting mitochondrial apoptotic cascades.
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http://dx.doi.org/10.3390/ijms18091947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618596PMC
September 2017

A pairwise likelihood augmented Cox estimator for left-truncated data.

Biometrics 2018 03 29;74(1):100-108. Epub 2017 Aug 29.

Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, U.S.A.

Survival data collected from a prevalent cohort are subject to left truncation and the analysis is challenging. Conditional approaches for left-truncated data could be inefficient as they ignore the information in the marginal likelihood of the truncation times. Length-biased sampling methods may improve the estimation efficiency but only when the underlying truncation time is uniform; otherwise, they may generate biased estimates. We propose a semiparametric method for left-truncated data under the Cox model with no parametric distributional assumption about the truncation times. Our approach is to make inference based on the conditional likelihood augmented with a pairwise likelihood, which eliminates the truncation distribution, yet retains the information about the regression coefficients and the baseline hazard function in the marginal likelihood. An iterative algorithm is provided to solve for the regression coefficients and the baseline hazard function simultaneously. By empirical process and U-process theories, it has been shown that the proposed estimator is consistent and asymptotically normal with a closed-form consistent variance estimator. Simulation studies show substantial efficiency gain of our estimator in both the regression coefficients and the cumulative baseline hazard function over the conditional approach estimator. When the uniform truncation assumption holds, our estimator enjoys smaller biases and efficiency comparable to that of the full maximum likelihood estimator. An application to the analysis of a chronic kidney disease cohort study illustrates the utility of the method.
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http://dx.doi.org/10.1111/biom.12746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402872PMC
March 2018

A C-index for recurrent event data: Application to hospitalizations among dialysis patients.

Biometrics 2018 06 3;74(2):734-743. Epub 2017 Aug 3.

Arbor Research Collaborative for Health, Ann Arbor, Michigan 48104, U.S.A.

We propose a C-index (index of concordance) applicable to recurrent event data. The present work addresses the dearth of measures for quantifying a regression model's ability to discriminate with respect to recurrent event risk. The data which motivated the methods arise from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a long-running prospective international study of end-stage renal disease patients on hemodialysis. We derive the theoretical properties of the measure under the proportional rates model (Lin et al., 2000), and propose computationally convenient inference procedures based on perturbed influence functions. The methods are shown through simulations to perform well in moderate samples. Analysis of hospitalizations among a cohort of DOPPS patients reveals substantial improvement in discrimination upon adding country indicators to a model already containing basic clinical and demographic covariates, and further improvement upon adding a relatively large set of comorbidity indicators.
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http://dx.doi.org/10.1111/biom.12761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647832PMC
June 2018