Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.

PURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

The predictive and prognostic role of hematologic and biochemical parameters in the emergency department among coronavirus disease 2019 patients.

Coronavirus disease 2019 (COVID-19) had caused a worldwide pandemic with public health emergencies since 2020. For the symptomatic patients, high mortality rate was observed if without timely and optimized management. In this study, we aimed to investigate the predictive and prognostic roles of hematologic and biochemical parameters obtained in the emergency department (ED) for COVID-19 patients. We conducted a retrospective study in a dedicated COVID-19 medical center, recruiting a total of 228 COVID-19 patients with 86 severe and 142 non-severe cases. Both the hematologic and biochemical parameters obtained in the ED upon arrival were analyzed to evaluate the association of the biomarkers with disease severity and prognosis among COVID-19 patients. Among these parameters, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, and D-dimer were significantly higher in the severe group than the non-severe one, whereas the platelet count and lymphocyte-to-monocyte ratio were significantly lower. Receiver operating characteristic curve analysis revealed that the areas under curve of CRP, PCT, LDH, ferritin, D-dimer, and NLR for differentiating the severity of COVID-19 were 0.713, 0.755, 0.763, 0.741, 0.733, and 0.683, respectively, whereas the areas under curve of CRP, PCT, LDH, ferritin, D-dimer, and NLR for differentiating the mortality of COVID-19 were 0.678, 0.744, 0.680, 0.676, 0.755, and 0.572, respectively. Logistic regression analysis revealed that CRP, PCT, LDH, ferritin, D-dimer, and NLR were independent indicators for prediction of severe COVID-19, and LDH and ferritin were independent factors associated with the mortality in COVID-19. In conclusion, higher CRP, PCT, LDH, ferritin, D-dimer, and NLR were associated with severe COVID-19, whereas higher LDH and ferritin were associated with the mortality in COVID-19. These findings could help early risk stratification in the ED and contribute to optimized patient management.

Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small. CONCLUSIONS: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.

MRI gadolinium dosing on basis of blood volume.

PURPOSE: Gadolinium-based contrast agents (GBCAs) for MRI are generally administrated in direct relationship to body weight. Instead, we propose a model for GBCA dosing on the basis of blood volume. The new method was tested by exploring the associations between MRI T1 mapping indices and weight in the MESA (Multi-Ethnic Study of Atherosclerosis. METHODS: Empirically derived methods based on sex and body habitus were used to calculate blood volumes. GBCA dose (in mL) in blood (in L) was calculated as the injected volume divided by the blood volume (i.e., DBV). Of the 1219 participants with cardiac MRI T1 mapping, 845 studies had standard dose of 0.15 mmol/kg (cohort 1) and 166 studies had 30 mL of GBCA regardless of weight (cohort 2). We also created a specific cohort with similar DBV (N = 357; cohort 3). RESULTS: Postcontrast blood relaxation rate R1blood and DBV were significantly correlated (R = 0.641; P < 0.001). R1blood was significantly associated with weight in cohort 1 and 2, but the correlation coefficient was positive for cohort 1 and negative for cohort 2, indicating GBCA overdosing in cohort 1 and underdosing in cohort 2 in heavy relative to lean subjects. R1blood was not associated with weight in cohort 3. Simulated results demonstrated that less contrast should be administrated for heavy subjects compared to the conventional weight-based dose. CONCLUSION: GBCA dosing on the basis of blood volume could improve the efficacy and safety of contrast-enhanced MRI studies. This method could be implemented to standardize dose and augment precision in study comparisons.

Antibacterial Property of Composites of Reduced Graphene Oxide with Nano-Silver and Zinc Oxide Nanoparticles Synthesized Using a Microwave-Assisted Approach.

Graphene oxide (GO) composites with various metal nanoparticles (NPs) are attracting increasing interest owing to their broad scope in biomedical applications. Here, microwave-assisted chemical reduction was used to deposit nano-silver and zinc oxide NPs (Ag and ZnO NPs) on the surface of reduced GO (rGO) at the following weight percentages: 5.34% Ag/rGO, 7.49% Ag/rGO, 6.85% ZnO/rGO, 16.45% ZnO/rGO, 3.47/34.91% Ag/ZnO/rGO, and 7.08/15.28% Ag/ZnO/rGO. These materials were tested for antibacterial activity, and 3.47/34.91% Ag/ZnO/rGO and 7.08/15.28% Ag/ZnO/rGO exhibited better antibacterial activity than the other tested materials against the gram-negative bacterium Escherichia coli K12. At 1000 ppm, both these Ag/ZnO/rGO composites had better killing properties against both E. coli K12 and the gram-positive bacterium Staphylococcus aureus SA113 than Ag/rGO and ZnO/rGO did. RedoxSensor flow cytometry showed that 3.47/34.91% Ag/ZnO/rGO and 7.08/15.28% Ag/ZnO/rGO decreased reductase activity and affected membrane integrity in the bacteria. At 100 ppm, these two composites affected membrane integrity more in E. coli, while 7.08/15.28% Ag/ZnO/rGO considerably decreased reductase activity in S. aureus. Thus, the 3.47/34.91% and 7.08%/15.28% Ag/ZnO/rGO nanocomposites can be applied not only as antibacterial agents but also in a variety of biomedical materials such as sensors, photothermal therapy, drug delivery, and catalysis, in the future.

Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia.

BACKGROUND: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes. OBJECTIVE: To evaluate the safety and efficacy of long-term CSHI. DESIGN: Single-centre, open-label, phase 2 extension study. PATIENTS: Five adults with classic CAH. MEASUREMENTS: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates. RESULTS: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 ± 8.8 vs 33.6 ± 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported. CONCLUSIONS: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term.

Pulmonary artery stiffness in chronic obstructive pulmonary disease (COPD) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) and particularly emphysema are characterized by stiffness of the aorta, due in part to accelerated elastin degradation in the lungs and aorta. Stiffness of the pulmonary arteries (PAs) may also be increased in COPD and emphysema, but data are lacking. We assessed PA stiffness using MRI in patients with COPD and related these measurements to COPD severity and percent emphysema. MATERIALS AND METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 290 participants, age 50-79 years with 10 or more packyears and free of clinical cardiovascular disease. COPD severity were defined on postbronchodilator spirometry by ATS/ERS criteria. Percent emphysema was defined as the percentage of regions of the lung < -950 Hounsfield units on full-lung computed tomography (CT). PA stain was defined by the percent change in cross-sectional PA area between systole and diastole on MRI. Blood flow across the tricuspid and mitral valves was assessed by phase-contrast MRI for determination of the ventricular diastolic dysfunction (E/A ratio). RESULTS: PA strain was reduced in COPD compared with controls (P = 0.002) and was inversely correlated with COPD severity (P = 0.004). PA strain was inversely associated to percent emphysema (P = 0.01). PA strain was also markedly correlated with right ventricular diastolic dysfunction measured by E/A ratios in the fully adjusted mix models (P = 0.02). CONCLUSION: PA strain is reduced in COPD, related in part to percent emphysema on CT scan, which may have implications for pulmonary small vessel flow and right ventricular function. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:262-271.

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy. METHODS: Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. RESULTS: The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. CONCLUSIONS: The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations.

Hypertrabeculated Left Ventricular Myocardium in Relationship to Myocardial Function and Fibrosis: The Multi-Ethnic Study of Atherosclerosis.

Purpose To determine if excess greater left ventricle (LV) trabeculation is associated with decreased average regional myocardial function, diffuse fibrosis, or both. Materials and Methods This was a HIPAA-compliant institutional board approved multicenter study, and all participants provided written informed consent. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) underwent a comprehensive cardiac magnetic resonance (MR) examination. LV trabeculation was measured with the maximal apical fractal dimension (FD), which is a marker of endocardial complexity. Demographic covariates, cardiovascular risk factors, and cardiac MR measurements were compared across quartiles of FD. Associations between FD and peak regional systolic circumferential strain (Ecc) and T1 time, a surrogate for diffuse myocardial fibrosis, were assessed with multivariable linear regression models. Results A total of 1123 subjects (593 [52.8%] female; mean age, 67.1 years ± 8.7 [standard deviation]) underwent FD and Ecc measurement, and 992 (521 [52.5%] female; mean age, 67.1 years ± 8.7) underwent FD and T1 measurement. Mean FD was 1.2 ± 0.07 in both groups, and mean Ecc was -18.3 ± 2.27 in the subjects who underwent FD and Ecc measurement. Global volumes and ejection fraction showed no differences between FD quartiles. However, with increasing FD quartile, Ecc was greater (indicating worse average regional function) (P < .001). After adjustment, greater trabeculation was associated with 21% worse myocardial strain (relative to the mean) per unit change in FD (regression coefficient = 4.0%; P < .001). There was no association between the degree of trabeculation and diffuse fibrosis measured with T1 mapping. Conclusion Average regional LV function was worse in individuals with greater LV trabeculation, supporting the concept of hypertrabeculation being an epiphenomenon of disease. © RSNA, 2017.

Electrocardiographic Impact of Myocardial Diffuse Fibrosis and Scar: MESA (Multi-Ethnic Study of Atherosclerosis).

Purpose To examine the associations of myocardial diffuse fibrosis and scar with surface electrocardiographic (ECG) parameters in individuals free of prior coronary heart disease in four different ethnicities. Materials and Methods This prospective cross-sectional study was approved by the institutional review boards, and all participants gave informed consent. A total of 1669 participants in the Multi-Ethnic Study of Atherosclerosis, or MESA, who were free of prior myocardial infarction underwent both ECG and cardiac magnetic resonance imaging. In individuals without a late gadolinium enhancement-defined myocardial scar (n = 1131), T1 mapping was used to assess left ventricular (LV) interstitial diffuse fibrosis. The associations of LV diffuse fibrosis or myocardial scar with ECG parameters (QRS voltage, QRS duration, and corrected QT interval [QTc]) were evaluated by using multivariable regression analyses adjusted for demographic data, risk factors for scar, LV end-diastolic volume, and LV mass. Results The mean age of the 1669 participants was 67.4 years ± 8.7 (standard deviation); 49.8% were women. Lower postcontrast T1 time at 12 minutes was significantly associated with lower QRS Sokolow-Lyon voltage (ß = 15.1 µV/10 msec, P = .004), lower QRS Cornell voltage (ß = 9.2 µV/10 msec, P = .031), and shorter QRS duration (ß = 0.16 msec/10 msec, P = .049). Greater extracellular volume (ECV) fraction was also significantly associated with lower QRS Sokolow-Lyon voltage (ß = -35.2 µV/1% ECV increase, P < .001) and Cornell voltage (ß = -23.7 µV/1% ECV increase, P < .001), independent of LV structural indexes. In contrast, the presence of LV scar (n = 106) was associated with longer QTc (ß = 4.3 msec, P = .031). Conclusion In older adults without prior coronary heart disease, underlying greater LV diffuse fibrosis is associated with lower QRS voltage and shorter QRS duration at surface ECG, whereas clinically unrecognized myocardial scar is associated with a longer QT interval. © RSNA, 2016 Online supplemental material is available for this article.

ISMRM Raw data format: A proposed standard for MRI raw datasets.

PURPOSE: This work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algorithm and data sharing. METHODS: A file format consisting of a flexible header and tagged frames of k-space data was designed. Application Programming Interfaces were implemented in C/C++, MATLAB, and Python. Converters for Bruker, General Electric, Philips, and Siemens proprietary file formats were implemented in C++. Raw data were collected using magnetic resonance imaging scanners from four vendors, converted to ISMRM Raw Data format, and reconstructed using software implemented in three programming languages (C++, MATLAB, Python). RESULTS: Images were obtained by reconstructing the raw data from all vendors. The source code, raw data, and images comprising this work are shared online, serving as an example of an image reconstruction project following a paradigm of reproducible research. CONCLUSION: The proposed raw data format solves a practical problem for the magnetic resonance imaging community. It may serve as a foundation for reproducible research and collaborations. The ISMRM Raw Data format is a completely open and community-driven format, and the scientific community is invited (including commercial vendors) to participate either as users or developers. Magn Reson Med 77:411-421, 2017. © 2016 Wiley Periodicals, Inc.

Screening for Cardiac Magnetic Resonance Scar Features by 12-Lead ECG, in Patients with Preserved Ejection Fraction.

BACKGROUND: Increased QRS score and wide spatial QRS-T angle are independent predictors of cardiovascular mortality in the general population. Our main objective was to assess whether a QRS score ≥ 5 and/or QRS-T angle ≥ 105° enable screening of patients for myocardial scar features. METHODS: Seventy-seven patients of age ≤ 70 years with QRS score ≥ 5 and/or spatial QRS-T angle ≥ 105° as well as left ventricular ejection fraction (LVEF) >35% were enrolled in the study. All participants underwent complete clinical examination, signal-averaged ECG (SAECG), 30-minute ambulatory ECG recording for T-wave alternans (TWA), and late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Relationship between QRS score, QRS-T angle with scar presence and pattern, as well as gray zone, core, and total scar size by LGE-CMR were assessed. RESULTS: Myocardial scar was present in 41 (53%) patients, of whom 19 (46%) exhibited a typical ischemic pattern. QRS score but not QRS-T angle was related to total scar size and gray zone size (R(2) = 0.12, P = 0.002; R(2) = 0.17; P ≤ 0.0001, respectively). Patients with QRS scores ≥ 6 had significantly greater myocardial scar and gray zone size, increased QRS duration and QRS-T angle, a higher prevalence of late potentials (LPs) presence, increased LV end-diastolic volume and decreased LVEF. There was a significant independent and positive association between TWA value and total scar (P = 0.001) and gray zone size (P = 0.01). CONCLUSION: Patients with preserved LVEF and myocardial scar by CMR also have electrocardiographic features that could be involved in ventricular arrhythmogenesis.

Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults.

BACKGROUND: Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction. METHODS: A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI. RESULTS: Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [±SD], 21.7 ± 8.6% vs 30.5 ± 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P ≤ .04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02). CONCLUSIONS: HIV-infected adults have reduced myocardial function as compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid levels and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV-infected individuals.

The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T1 mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis. METHODS: CVD risk scores for 1208 subjects (men, 50.8%) ages 55-94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T1 times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T1, 12 and 25 minute post-gadolinium T1, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001). RESULTS: 25 minute post gadolinium T1 time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e.g. native T1 (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index. CONCLUSIONS: Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T1 times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T1 time. CLINICAL TRIAL REGISTRATION: http://www.mesa-nhlbi.org/, NCT00005487.

Prevalence and Correlates of Myocardial Scar in a US Cohort.

IMPORTANCE: Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using contemporary methods in a multiethnic US population. OBJECTIVE: To determine prevalence of and factors associated with myocardial scar in middle- and older-aged individuals in the United States. DESIGN, SETTING, AND PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA) study is a population-based cohort in the United States. Participants were aged 45 through 84 years and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination (2010-2012), 1840 participants underwent cardiac magnetic resonance (CMR) imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios (ORs) for myocardial scar. EXPOSURES: Cardiovascular risk factors, CAC scores, left ventricle size and function, and carotid intima-media thickness. MAIN OUTCOMES AND MEASURES: Myocardial scar detected by CMR imaging. RESULTS: Of 1840 participants (mean [SD] age, 68 [9] years, 52% men), 146 (7.9%) had myocardial scars, of which 114 (78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male sex, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10. The OR per 8.9-year increment was 1.61 (95% CI, 1.36-1.91; P < .001); for men vs women: OR, 5.76 (95% CI, 3.61-9.17; P < .001); per 4.8-SD body mass index: OR, 1.32 (95% CI, 1.09-1.61, P = .005); for hypertension: OR, 1.61 (95% CI, 1.12-2.30; P = .009); and for current vs never smokers: 2.00 (95% CI, 1.22-3.28; P = .006). Age-, sex-, and ethnicity-adjusted CAC scores at baseline were also associated with myocardial scar at year 10. Compared with a CAC score of 0, the OR for scores from 1 through 99 was 2.4 (95% CI, 1.5-3.9); from 100 through 399, 3.0 (95% CI, 1.7-5.1), and 400 or higher, 3.3 (95% CI, 1.7-6.1) (P ≤ .001). The CAC score significantly added to the association of myocardial scar with age, sex, race/ethnicity, and traditional CVD risk factors (C statistic, 0.81 with CAC vs 0.79 without CAC, P = .01). CONCLUSIONS AND RELEVANCE: The prevalence of myocardial scars in a US community-based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars.

Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study.

BACKGROUND: Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. METHODS AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2-12; P=0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3-11; P<0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume (P=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009). CONCLUSIONS: Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.

Antifungal susceptibilities of Candida isolates causing bloodstream infections at a medical center in Taiwan, 2009-2010.

We used the Sensititre YeastOne (SYO) method (Trek Diagnostic Systems) to determine the MICs of nine antifungal agents against 474 nonduplicate blood Candida isolates. The MIC results were interpreted according to updated clinical breakpoints (CBPs) recommended by the Clinical and Laboratory Standards Institute (CLSI; document M27-S4) or epidemiology cutoff values (ECVs). The rates of fluconazole susceptibility were 99.2% (234/236) in Candida albicans, 86.7% (85/98) in C. tropicalis, and 97.7% (42/43) in C. parapsilosis. Among the 77 isolates of C. glabrata, 90.9% showed dose-dependent susceptibility (S-DD) to fluconazole. Nearly all isolates of C. albicans, C. parapsilosis, and C. krusei were susceptible to voriconazole; however, rates of voriconazole susceptibility were 78.6% in C. tropicalis. Few isolates of C. albicans (n = 5; 2.1%) and C. glabrata (n = 3; 3.9%), no isolates of C. parapsilosis, C. krusei, and C. guilliermondii, but 62.2% (n = 51) of C. tropicalis isolates were non-wild type for posaconazole susceptibility. For itraconazole susceptibility, 98.3% of C. albicans isolates were wild type, and 3.9% (n = 3) of C. glabrata isolates were non-wild type. Almost all of the isolates tested (>97% for all species) were susceptible to both micafungin and anidulafungin. All isolates tested were found to be wild type for amphotericin B susceptibility, with MICs of <1 µg/ml. Further evaluation is needed to establish CBPs of antifungal agents by the 24-h SYO method for the management of patients with candidemia or other invasive candida infections.

Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study.

RATIONALE: Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking. OBJECTIVES: We hypothesized that levels of CD31(+) EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined. METHODS: The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50-79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31(+) EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E(+) EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than -950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors. MEASUREMENTS AND MAIN RESULTS: CD31(+) EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31(+) EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P = 0.01). In contrast, CD62E(+) EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001). CONCLUSIONS: CD31(+) EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E(+) EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation.

Mortality of continuous infusion versus intermittent bolus of meropenem: a systematic review and meta-analysis of randomized controlled trials.

Background: Meropenem belongs to the carbapenem class, which is categorized as beta-lactam antibiotics. These antibiotics are administered in intermittent bolus doses at specific time intervals. However, the continuous infusion approach ensures sustained drug exposure, maintaining the drug concentration above the minimum inhibitory concentration (MIC) throughout the entire treatment period. This study aimed to find out the association between continuous infusions of meropenem and mortality rates. Materials and methods: We conducted a search of the PubMed/Medline, EMBASE, Cochrane Central, and ClinicalTrials.gov databases up to 14 August 2023. The six randomized controlled trials (RCTs) were identified and included in our analysis. The random-effects model was implemented using Comprehensive Meta-Analysis software to examine the outcomes. Results: Our study included a total of 1,529 adult patients from six randomized controlled trials. The primary outcome indicated that continuous infusion of meropenem did not lead to reduction in the mortality rate (odds ratio = 0.844, 95% CI: 0.671-1.061, P =0.147). Secondary outcomes revealed no significant differences in ICU length of stay (LOS), ICU mortality, clinical cure, or adverse events between continuous infusion and traditional intermittent bolus strategies of meropenem. Notably, we observed significant improvements in bacterial eradication (odds ratio 19 = 2.207, 95% CI: 1.467-3.320, P < 0.001) with continuous infusion of meropenem. Our study also suggested that performing continuous infusion may lead to better bacterial eradication effects in resistant pathogens (coefficient: 2.5175, P = 0.0138*). Conclusion: Continuous infusion of meropenem did not result in the reduction of mortality rates but showed potential in improving bacterial eradication. Furthermore, this strategy may be particularly beneficial for achieving better bacterial eradication, especially in cases involving resistant pathogens.