Publications by authors named "K W Im"

607 Publications

Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2021 Apr 14. Epub 2021 Apr 14.

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.

Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).

Design, Setting, And Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018.

Interventions: Dapagliflozin vs placebo.

Main Outcomes And Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.

Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.

Conclusions And Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.

Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.
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http://dx.doi.org/10.1001/jamacardio.2021.0660DOI Listing
April 2021

Association between Quantitative MR Markers of Cortical Evolving Organization and Gene Expression during Human Prenatal Brain Development.

Cereb Cortex 2021 Apr 9. Epub 2021 Apr 9.

The Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Boston, MA 02115, USA.

The relationship between structural changes of the cerebral cortex revealed by Magnetic Resonance Imaging (MRI) and gene expression in the human fetal brain has not been explored. In this study, we aimed to test the hypothesis that relative regional thickness (a measure of cortical evolving organization) of fetal cortical compartments (cortical plate [CP] and subplate [SP]) is associated with expression levels of genes with known cortical phenotype. Mean regional SP/CP thickness ratios across age measured on in utero MRI of 25 healthy fetuses (20-33 gestational weeks [GWs]) were correlated with publicly available regional gene expression levels (23-24 GW fetuses). Larger SP/CP thickness ratios (more pronounced cortical evolving organization) was found in perisylvian regions. Furthermore, we found a significant association between SP/CP thickness ratio and expression levels of the FLNA gene (mutated in periventricular heterotopia, congenital heart disease, and vascular malformations). Further work is needed to identify early MRI biomarkers of gene expression that lead to abnormal cortical development.
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http://dx.doi.org/10.1093/cercor/bhab035DOI Listing
April 2021

Impact of motor subtype on non-motor symptoms and fall-related features in patients with early Parkinson's disease.

Geriatr Gerontol Int 2021 Mar 29. Epub 2021 Mar 29.

Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, Taiwan.

Aim: Clinical implications for motor phenotypes of Parkinson's disease (PD) remain to be further elucidated, particularly at the early stages of the disease. We aimed to compare the non-motor and fall-related features between tremor-dominant (TD) and postural instability-gait difficulty (PIGD) subtypes in patients with early PD.

Methods: PD was categorized into TD, intermediate and PIGD types, according to the literature. Not only motor symptoms, but also non-motor symptoms for global cognition, depression, anxiety, fatigue and dysautonomia, were measured in detail. In addition, fall-related features, including a previous history of falls, fear of fall measurement and gait freezing were assessed.

Results: In patients with early PD (disease duration no more than 5 years), 35 patients with TD-type PD and 31 patients with PIGD-type PD were finally evaluated for the study. Compared with the TD group, the PIGD group showed higher fatigue, gastrointestinal dysfunction and fall-related parameter scores. Moreover, the PIGD scores were significantly correlated with all of those symptoms.

Conclusions: Our findings suggest that PIGD is significantly linked to fatigue, gastrointestinal dysfunction and fall-related features during the early stages of PD. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2021; ••: ••-••.
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http://dx.doi.org/10.1111/ggi.14156DOI Listing
March 2021

Abnormal Left-Hemispheric Sulcal Patterns in Adults With Simple Congenital Heart Defects Repaired in Childhood.

J Am Heart Assoc 2021 Apr 22;10(7):e018580. Epub 2021 Mar 22.

Department of Clinical Medicine Aarhus University Aarhus N Denmark.

Background Children operated on for a simple congenital heart defect (CHD) are at risk of neurodevelopmental abnormalities. Abnormal cortical development and folding have been observed in fetuses with CHD. We examined whether sulcal folding patterns in adults operated on for simple CHD in childhood differ from those of healthy controls, and whether such differences are associated with neuropsychological outcomes. Methods and Results Patients (mean age, 24.5 years) who underwent childhood surgery for isolated atrial septal defect (ASD; n=33) or ventricular septal defect (VSD; n=30) and healthy controls (n=37) were enrolled. Sulcal pattern similarity to healthy controls was determined using magnetic resonance imaging and looking at features of sulcal folds, their intersulcal relationships, and sulcal graph topology. The sulcal pattern similarity values were tested for associations with comprehensive neuropsychological scores. Patients with both ASD and VSD had decreased sulcal pattern similarity in the left hemisphere compared with controls. The differences were found in the left temporal lobe in the ASD group and in the whole left hemisphere in the VSD group (=0.033 and =0.039, respectively). The extent of abnormal left hemispheric sulcal pattern similarity was associated with worse neuropsychological scores (intelligence, executive function, and visuospatial abilities) in the VSD group, and special educational support in the ASD group. Conclusions Adults who underwent surgery for simple CHD in childhood display altered left hemisphere sulcal folding patterns, commensurate with neuropsychological scores for patients with VSD and special educational support for ASD. This may indicate that simple CHD affects early brain development. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.
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http://dx.doi.org/10.1161/JAHA.120.018580DOI Listing
April 2021

Cortical Subarachnoid Hemorrhage Presenting with Hemibody Dystonic Myoclonus: An Illustrative Case.

J Mov Disord 2021 Mar 15. Epub 2021 Mar 15.

Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.14802/jmd.20127DOI Listing
March 2021

Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials.

Circulation 2021 Feb 15;143(7):685-695. Epub 2021 Feb 15.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (E.B., D.A.M., R.P.G., E.M.A., B.M.S., E.A.B., S.D.W., K.I., J.G., M.S.S., M.O.D.).

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown.

Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models.

Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR], 1.22 [95% CI, 1.16-1.28]; <0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (OR, 1.20 [95% CI, 1.13-1.27]) and active therapy arms (OR, 1.23 [95% CI, 1.17-1.30)]; there was some evidence for regional heterogeneity ( interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; =0.60). Women were also more likely to withdraw consent compared with men (OR, 1.26 [95% CI, 1.17-1.36]; <0.001).

Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894618PMC
February 2021

Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long-Term Ticagrelor in Stable Patients With Prior Myocardial Infarction.

J Am Heart Assoc 2021 Feb 9;10(4):e017008. Epub 2021 Feb 9.

University of ColoradoSchool of Medicine Aurora CO.

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long-term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3-fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; =0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65-0.96; interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/. Unique identifier: NCT01225562.
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http://dx.doi.org/10.1161/JAHA.120.017008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955333PMC
February 2021

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

In Vitro and In Vivo Medicinal Value of Culinary-Medicinal Lung Oyster Mushroom Pleurotus pulmonarius var. stechangii (Agaricomycetes).

Int J Med Mushrooms 2020 ;22(8):763-774

Division of Life Sciences, Incheon National University, (Songdo-dong) 119 Academy-ro, Yeonsu-gu, Incheon 22012, Korea.

Pleurotus pulmonarius var. stechangii is a culinary-medicinal mushroom commonly cultivated in subtropical countries in Asia. In this study, the in vitro antixanthine oxidase, antihyperglycemic, and in vivo anti-inflammatory activities of a methanol extract (ME) of P. pulmonarius var. stechangii fruiting bodies were evaluated. The xanthine oxidase inhibitory activity of the ME of P. pulmonarius var. stechangii was lower than that of allopurinol, a xanthine oxidase inhibitor used as a positive control. Eleven phenolic compounds were identified from the fruiting bodies of P. pulmonarius var. stechangii by HPLC analysis. The inhibitory effects of ME on α-amylase and α-glucosidase were moderate and lower than that of acarbose, a positive control. The ME inhibited the production of nitric oxide (NO) and nitric oxide synthases (iNOS) protein expression in lipopolysaccharide-induced RAW 264.7 macrophages. It also exhibited an inhibitory effect on carrageenan-induced hind paw edema in a rat model. Taken together, our experimental results demonstrated that the fruiting bodies of P. pulmonarius var. stechangii might be a good natural source to promote human health through its antixanthine oxidase, antihyperglycemia, and anti-inflammatory activities.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2020035566DOI Listing
January 2020

Ultradeep Sequencing Analysis of Paroxysmal Nocturnal Hemoglobinuria Clones Detected by Flow Cytometry: PIG Mutation in Small PNH Clones.

Am J Clin Pathol 2020 Dec 21. Epub 2020 Dec 21.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea.

Objectives: We aimed to determine whether small paroxysmal nocturnal hemoglobinuria (PNH) clones detected by flow cytometry (FCM) harbor PIG gene mutations with quantitative correlation.

Methods: We analyzed 89 specimens from 63 patients whose PNH clone size was ≥0.1% by FCM. We performed ultradeep sequencing for the PIGA, PIGM, PIGT, and PIGX genes in these specimens.

Results: A strong positive correlation between PNH clone size by FCM and variant allele frequency (VAF) of PIG gene mutation was identified (RBCs: r = 0.77, P < .001; granulocytes: r = 0.68, P < .001). Granulocyte clone size of 2.5% or greater and RBCs 0.4% or greater by FCM always harbored PIG gene mutations. Meanwhile, in patients with clone sizes of less than 2.5% in granulocytes or less than 0.4% in RBCs, PIG gene mutations were present in only 15.9% and 12.2% of cases, respectively. In addition, there was not a statistically significant positive correlation between FCM clone size and VAF or the presence or absence of a PIG mutation.

Conclusions: Our results showed that in small PNH clones PIG gene mutations were present in only a small portion without significant correlation to VAF or the presence or absence of a PIG mutation.
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http://dx.doi.org/10.1093/ajcp/aqaa211DOI Listing
December 2020

Fetal Cortical Plate Segmentation Using Fully Convolutional Networks With Multiple Plane Aggregation.

Front Neurosci 2020 2;14:591683. Epub 2020 Dec 2.

Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.

Fetal magnetic resonance imaging (MRI) has the potential to advance our understanding of human brain development by providing quantitative information of cortical plate (CP) development . However, for a reliable quantitative analysis of cortical volume and sulcal folding, accurate and automated segmentation of the CP is crucial. In this study, we propose a fully convolutional neural network for the automatic segmentation of the CP. We developed a novel hybrid loss function to improve the segmentation accuracy and adopted multi-view (axial, coronal, and sagittal) aggregation with a test-time augmentation method to reduce errors using three-dimensional (3D) information and multiple predictions. We evaluated our proposed method using the ten-fold cross-validation of 52 fetal brain MR images (22.9-31.4 weeks of gestation). The proposed method obtained Dice coefficients of 0.907 ± 0.027 and 0.906 ± 0.031 as well as a mean surface distance error of 0.182 ± 0.058 mm and 0.185 ± 0.069 mm for the left and right, respectively. In addition, the left and right CP volumes, surface area, and global mean curvature generated by automatic segmentation showed a high correlation with the values generated by manual segmentation ( > 0.941). We also demonstrated that the proposed hybrid loss function and the combination of multi-view aggregation and test-time augmentation significantly improved the CP segmentation accuracy. Our proposed segmentation method will be useful for the automatic and reliable quantification of the cortical structure in the fetal brain.
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http://dx.doi.org/10.3389/fnins.2020.591683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738480PMC
December 2020

Intergenerational Transmission of Cortical Sulcal Patterns from Mothers to their Children.

Cereb Cortex 2021 Mar;31(4):1888-1897

Fetal-Neonatal Neuroimaging & Developmental Science Center, Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.

Intergenerational effects are described as the genetic, epigenetic, as well as pre- and postnatal environmental influence parents have on their offspring's behavior, cognition, and brain. During fetal brain development, the primary cortical sulci emerge with a distinctive folding pattern that are under strong genetic influence and show little change of this pattern throughout postnatal brain development. We examined intergenerational transmission of cortical sulcal patterns by comparing primary sulcal patterns between children (N = 16, age 5.5 ± 0.81 years, 8 males) and their biological mothers (N = 15, age 39.72 ± 4.68 years) as well as between children and unrelated adult females. Our graph-based sulcal pattern comparison method detected stronger sulcal pattern similarity for child-mother pairs than child-unrelated pairs, where higher similarity between child-mother pairs was observed mostly for the right lobar regions. Our results also show that child-mother versus child-unrelated pairs differ for daughters and sons with a trend toward significance, particularly for the left hemisphere lobar regions. This is the first study to reveal significant intergenerational transmission of cortical sulcal patterns, and our results have important implications for the study of the heritability of complex behaviors, brain-based disorders, the identification of biomarkers, and targets for interventions.
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http://dx.doi.org/10.1093/cercor/bhaa328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945013PMC
March 2021

Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials.

Lancet 2020 11 10;396(10263):1637-1643. Epub 2020 Nov 10.

TIMI Study Group, Division of Cardiovascular Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.

Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol.

Findings: Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61-0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78-0·92]; p=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73-0·91]) and non-statin treatment (0·67 [0·47-0·95]; p=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74-0·98]), myocardial infarction (0·80 [0·71-0·90]), stroke (0·73 [0·61-0·87]), and coronary revascularisation (0·80 [0·66-0·96]).

Interpretation: In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32332-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015314PMC
November 2020

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BMC Med Genomics 2020 11 4;13(1):165. Epub 2020 Nov 4.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Background: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.

Methods: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.

Results: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.

Conclusions: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
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http://dx.doi.org/10.1186/s12920-020-00809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640690PMC
November 2020

A Case Report of Wall-Eyed Bilateral Internuclear Ophthalmoplegia with Bilateral Facial Palsy.

J Stroke Cerebrovasc Dis 2020 Nov 6;29(11):105139. Epub 2020 Aug 6.

Departments of Neurology, Soonchunhyang University School of Medicine, 59 Daesakwan-ro, Yong san-gu, Seoul 04401, South Korea. Electronic address:

Case reports of bilateral facial palsy with horizontal gaze restriction are rare. A 62-year-old woman experienced sudden onset of bilateral adduction deficits, bilateral abducting nystagmus accompanied with facial diplegia. We confirmed acute ischemic stroke in the midline dorsal pons, where medial longitudinal fasciculus (MLF) and facial nerve fascicles are located. This can be explained by vascular variation of pontine perforating arteries.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105139DOI Listing
November 2020

Human mesenchymal stem cells derived from umbilical cord and bone marrow exert immunomodulatory effects in different mechanisms.

World J Stem Cells 2020 Sep;12(9):1032-1049

Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.

Background: Mesenchymal stem cells (MSCs) are an attractive tool to treat graft-versus-host disease because of their unique immunoregulatory properties. Although human bone marrow-derived MSCs (BM-MSCs) were the most widely used MSCs in cell therapy until recently, MSCs derived from human umbilical cords (UC-MSCs) have gained popularity as cell therapy material for their ethical and noninvasive collection.

Aim: To investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.

Methods: To analyze soluble factors expressed by MSCs, such as indolamine 2,3-dioxygenase, cyclooxygenase-2, prostaglandin E2 and interleukin (IL)-6, inflammatory environments were reconstituted with combinations of interferon-gamma (IFN-γ), tumor necrosis factor alpha and IL-1β or with IFN-γ alone. Activated T cells were cocultured with MSCs treated with indomethacin and/or anti-IL-10. To assess the ability of MSCs to inhibit T helper 17 cells and induce regulatory T cells, induced T helper 17 cells were cocultured with MSCs treated with indomethacin or anti-IL-10. Xenogeneic graft-versus-host disease was induced in NOG mice (NOD/Shi-/IL-2Rγ) and UC-MSCs or BM-MSCs were treated as cell therapies.

Results: Our data demonstrated that BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunomodulation abilities. BM-MSCs expressed more indolamine 2,3-dioxygenase after cytokine stimulation with different combinations of IFN-γ, tumor necrosis factor alpha-α and IL-1β or IFN-γ alone. UC-MSCs expressed more prostaglandin E2, IL-6, programmed death-ligand 1 and 2 in the inflammatory environment. Cyclooxygenase-2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs. In addition, UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs. UC-MSCs and BM-MSCs exhibited similar effects on attenuating graft-versus-host disease.

Conclusion: UC-MSCs and BM-MSCs exert similar immunosuppressive effects with different mechanisms involved. These findings suggest that UC-MSCs have distinct immunoregulatory functions and may substitute BM-MBSCs in the field of cell therapy.
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http://dx.doi.org/10.4252/wjsc.v12.i9.1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524695PMC
September 2020

A Case of Polyneuritis Cranialis with the Initial Symptom of Isolated Hypoglossal Nerve Palsy.

J Clin Neurol 2020 Oct;16(4):702-703

Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3988/jcn.2020.16.4.702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541992PMC
October 2020

Efficacy of a novel extract of fenugreek seeds in alleviating vasomotor symptoms and depression in perimenopausal women: A randomized, double-blinded, placebo-controlled study.

J Food Biochem 2020 12 6;44(12):e13507. Epub 2020 Oct 6.

Akay Natural Ingredients Pvt. Ltd., Cochin, India.

The present randomized, double-blinded, placebo-controlled study investigated the effect of a standardized fenugreek extract (FHE) on perimenopausal discomforts and its influence on hormonal balance and safety. Healthy women characterized with perimenopausal symptoms (n = 48), as assessed by MRS questionnaire, were randomized either to FHE (n = 24) or placebo (n = 24) and supplemented with 250 mg × 2/day for 42 days. Both inter and intra-group comparison revealed a significant improvement in somatic, psychological, and urogenital scores in FHE group, especially for hot flashes (25.9%), night sweats (26.5%), depression (31.8%), and insomnia (21.6%). Further hormone analysis revealed an enhancement in serum estradiol (18.9%), free testosterone (38.2%), and progesterone (19.9%) concentrations and a significant decrease in FSH (38.2%) and SHBG (21.1%) concentrations toward establishing a hormonal balance among FHE-group; without significant changes in other clinical safety parameters. Thus, FHE supplementation offered a significant reduction in vasomotor effects and depression in perimenopausal women, without any adverse effects PRACTICAL APPLICATIONS: Fenugreek is a popular kitchen spice and Ayurvedic medicine for a variety of health conditions including diabetes, hypercholesterolemia, hepatotoxicity, gastritis, and also for a variety of hormone-related health conditions such as sexual functions, lactation, osteoporosis, PCOS, and post/perimenopausal discomforts. Fenugreek is rich in alkaloids, steroidal saponins, flavonoids and 4-hydroxyisoleucine. The present randomized-controlled study investigated the plausible application of a standardized hydro-ethanolic extract of fenugreek seeds (FHE) having a unique 3:1 ratio for protodioscin to trigonelline in the management of perimenopausal discomforts. It was observed that FHE at a dosage of 250 mg × 2/day for 42 days significantly reduced the discomforts, especially vasomotor symptoms and depression, and helped to attain a hormonal balance without any adverse effects or deviations in clinical safety parameters. Thus, FHE could be a potential natural agent for the management of post and perimenopausal discomforts and has to be explored in future studies.
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http://dx.doi.org/10.1111/jfbc.13507DOI Listing
December 2020

Diagnostic usefulness of putaminal abnormality on diffusion- and susceptibility-weighted imaging: two illustrative cases of multiple system atrophy-parkinsonian type.

Neurol Sci 2021 03 6;42(3):1211-1213. Epub 2020 Oct 6.

Department of Neurology, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea.

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http://dx.doi.org/10.1007/s10072-020-04770-2DOI Listing
March 2021

Regional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome.

Cereb Cortex 2021 Jan;31(2):757-767

Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Down syndrome (DS) is the most common genetic cause of developmental disabilities. Advanced analysis of brain magnetic resonance imaging (MRI) has been used to find brain abnormalities and their relationship to neurocognitive impairments in children and adolescents with DS. Because genetic factors affect brain development in early fetal life, there is a growing interest in analyzing brains from living fetuses with DS. In this study, we investigated regional sulcal folding depth as well as global cortical gyrification from fetal brain MRIs. Nine fetuses with DS (29.1 ± 4.24 gestational weeks [mean ± standard deviation]) were compared with 17 typically developing [TD] fetuses (28.4 ± 3.44). Fetuses with DS showed lower whole-brain average sulcal depths and gyrification index than TD fetuses. Significant decreases in sulcal depth were found in bilateral Sylvian fissures and right central and parieto-occipital sulci. On the other hand, significantly increased sulcal depth was shown in the left superior temporal sulcus, which is related to atypical hemispheric asymmetry of cortical folding. Moreover, these group differences increased as gestation progressed. This study demonstrates that regional sulcal depth is a sensitive marker for detecting alterations of cortical development in DS during fetal life, which may be associated with later neurocognitive impairment.
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http://dx.doi.org/10.1093/cercor/bhaa255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786357PMC
January 2021

Serum Metabolic Profiling Reveals Potential Anti-Inflammatory Effects of the Intake of Black Ginseng Extracts in Beagle Dogs.

Molecules 2020 Aug 18;25(16). Epub 2020 Aug 18.

Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Yeonsugu, Incheon 22012, Korea.

Black ginseng (BG) has better health benefits than white ginseng. The intake of BG changes the levels of metabolites, such as amino acids, fatty acids, and other metabolites. However, there is no research on the effect of BG extract intake on the metabolic profile of dog serum. In this study, serum metabolic profiling was conducted to investigate metabolic differences following the intake of BG extracts in beagle dogs. The beagle dogs were separated into three groups and fed either a regular diet (RD, control), RD with a medium concentration of BG extract (BG-M), or RD with a high concentration of BG extract (BG-H). Differences were observed among the three groups after the dogs ingested the experimental diet for eight weeks. The concentrations of alanine, leucine, isoleucine, and valine changed with the intake of BG extracts. Furthermore, levels of glycine and β-alanine increased in the BG-H group compared to the control and BG-M groups, indicating that BG extracts are associated with anti-inflammatory processes. Our study is the first to demonstrate the potential anti-inflammatory effect of BG extract in beagle dogs. Glycine and β-alanine are proposed as candidate serum biomarkers in dogs that can discriminate between the effects of ingesting BG-H.
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http://dx.doi.org/10.3390/molecules25163759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465512PMC
August 2020

An elderly man with normal pressure hydrocephalus presenting with asymmetric parkinsonism in the upper and lower extremities.

Geriatr Gerontol Int 2020 Aug;20(8):791-792

Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1111/ggi.13940DOI Listing
August 2020

Recent glycemic control can predict the progressive motor deficits of acute subcortical infarction with diabetes or prediabetes.

Neurol Sci 2021 Jan 31;42(1):285-291. Epub 2020 Jul 31.

Departments of Neurology, Soonchunhyang University School of Medicine, 59 Daesakwan-ro, Yong san-gu, Seoul, 04401, South Korea.

Background And Purpose: The predictors of progressive motor deficits in acute subcortical infarctions are still controversial. It is not known whether glycemic control influences on stroke progression.

Methods: A total of 268 consecutive patients with diabetes or prediabetes who had acute (< 24 h) subcortical infarction were enrolled. (1) All patients were divided into 4 groups by quartile of glycated hemoglobin (HbA1c). (2) Only the patients with diabetes were divided by effective glycemic control. Progressive motor deficits were prospectively captured and defined as an increase of motor score ≥ 1 on the upper or lower limb items of the National Institute of Health Stroke Scale within 72 h from stroke onset.

Results: Progressive motor deficits occur in 8/78 (10.3%) for ≤ 5.9, 15/61 (24.6%) for 6.0-6.4, 16/62 (25.8%) for 6.5-7.4, and 30/67 (44.8%) for ≥ 7.5. In diabetic patients alone, those occur in 5/37 (13.5%) for ≤ 6.5, 10/42 (23.8%) for 6.6-7.0, 12/42 (28.6%) for 7.1-8.0, and 24/50 (48.0%) for ≥ 8.1. An adjusted OR of progressive motor deficits was 2.61 (95% confidence interval [CI] 0.98-7.00, P = .056) for 6.0-6.4, 3.42 (95% CI 1.27-9.18, P = .015) for 6.5-7.4, and 6.65 (95% CI 2.38-18.62, P < .001) for ≥ 7.5. In diabetic patients alone, those were 3.15 (95% CI 0.89-11.15, P = .075) for 6.6-7.0, 2.90 (95% CI 0.79-10.61, P = .107) for 7.1-8.0, and 4.17 (95% CI 1.07-16.25, P = .038) for ≥ 8.1. The optimal cutoff value of HbA1c was 6.65% in discriminating progressive motor deficits.

Conclusion: Increased HbA1c was associated with higher incidence of progressive motor deficits in acute subcortical infarction with diabetes and prediabetes.
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http://dx.doi.org/10.1007/s10072-020-04634-9DOI Listing
January 2021

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease.

Int J Mol Sci 2020 Jul 26;21(15). Epub 2020 Jul 26.

School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.

Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has expanded to encompass neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), with related studies examining the functions of Igs in the central nervous system (CNS). Recent evidence suggests that Igs have various effects in the CNS; these effects are associated with the prevention of neurodegeneration, as well as induction. Here, we summarize the functional roles of Igs with respect to neurodegenerative disease (AD and PD), focusing on the target antigens and effector cell types. In addition, we review the current knowledge about the roles of these antibodies as diagnostic markers and immunotherapies.
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http://dx.doi.org/10.3390/ijms21155295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432158PMC
July 2020

Investigations on Metabolic Changes in Beagle Dogs Fed Probiotic Queso Blanco Cheese and Identification of Candidate Probiotic Fecal Biomarkers Using Metabolomics Approaches.

Metabolites 2020 Jul 25;10(8). Epub 2020 Jul 25.

Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Yeonsugu, Incheon 22012, Korea.

Intake of probiotic cheese improves the intestinal health of humans and animals. However, metabolic changes in the intestines of dogs in response to the ingestion of probiotic cheese have not been evaluated. Thus, we aimed to determine the metabolic changes in healthy beagle dogs fed queso blanco cheese with added KACC 92293 and KACC 91563 (QCLB) and to identify potential fecal biomarkers to distinguish the metabolic changes based on intake of probiotic cheese through metabolomics approaches. The dogs were randomly divided into three groups and fed a regular diet without any cheese (control), a diet with queso blanco cheese (QC), or one with QCLB for eight weeks. The concentrations of acetic, propionic, and 4-aminobutyric acids were increased in the QCLB group compared to those in the control group. Additionally, higher levels of propionic acid and lower levels of xylose were found in the QCLB group compared to those in the QC group. This is the first report on the identification of metabolic changes in beagle dogs fed queso blanco cheese with added KACC 92293 and KACC 91563. We also found that metabolomics approaches can be useful for identifying potential fecal markers in dogs fed probiotic cheese.
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http://dx.doi.org/10.3390/metabo10080305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464839PMC
July 2020

Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.

Aliment Pharmacol Ther 2020 09 23;52(5):808-820. Epub 2020 Jul 23.

Division of Digestive Diseases, Imperial College London, London, UK.

Background: In primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired.

Aims: To evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non-bile acid FXR agonist, in patients with primary bile acid diarrhoea.

Methods: In this double-blind, multicentre, randomised, cross-over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit.

Results: Twenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post-dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half-emptying time (P = 0.036).

Conclusions: Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea. ClinicalTrials.gov number: NCT02713243.
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http://dx.doi.org/10.1111/apt.15967DOI Listing
September 2020

Detailed visual assessment of striatal dopaminergic depletion in patients with idiopathic normal pressure hydrocephalus: unremarkable or not?

BMC Neurol 2020 Jul 11;20(1):277. Epub 2020 Jul 11.

Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea.

Background: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated.

Methods: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis.

Results: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved.

Conclusion: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.
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http://dx.doi.org/10.1186/s12883-020-01861-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353728PMC
July 2020

Investigation of Formation for Poly(vinylidene fluoride) Membrane Using Thermally Induced Phase Separation.

J Nanosci Nanotechnol 2020 Nov;20(11):7140-7144

Department of Material Engineering and Convergence Technology, Engineering Research Institute, Gyeongsang National University, Jinju, 52828, Korea.

In this study, thermally induced phase separation (TIPS) was used to fabricate a water treatment membrane composed of poly(vinylidene fluoride) (PVDF) and silica. Dioctyl phthalate (DOP) and dibutyl phthalate (DBP) were used as diluents. Crystallization temperature, cloud point, and morphology were observed to investigate the conditions of PVDF/silica/diluent membrane preparation. SEM revealed that the porosity of the membranes was increased with an increase in silica content. Phase diagram and morphology results revealed that 50 wt% PVDF+silica with a PVDF:silica weight ratio of 4.5:1 is the best composition for manufacturing a porous membrane.
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http://dx.doi.org/10.1166/jnn.2020.18829DOI Listing
November 2020