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.

A 19-year longitudinal study to characterize carbapenem-nonsusceptible Acinetobacter isolated from patients with bloodstream infections and the contribution of conjugative plasmids to carbapenem resistance and virulence.

BACKGROUND: This study aimed to characterize carbapenem-nonsusceptible Acinetobacter (CNSA) isolated from patients with bacteremia from 1997 to 2015. METHODS: A total of 173 CNSA (12.3%) was recovered from 1403 Acinetobacter isolates. The presence of selected ß-lactamase genes in CNSA was determined by PCR amplification. The conjugation test was used to determine the transferability of metallo-ß-lactamase (MBL)-carrying plasmids. Whole genome sequencing in combination with phenotypic assays was carried out to characterize MBL-plasmids. RESULTS: In general, a trend of increasing numbers of CNSA was observed. Among the 173 CNSA, A. baumannii (54.9%) was the most common species, followed by A. nosocomialis (23.1%) and A. soli (12.1%). A total of 49 (28.3%) CNSA were extensively drug-resistant, and all were A. baumannii. The most common class D carbapenemase gene in 173 CNSA was blaOXA-24-like (32.4%), followed by ISAba1-blaOXA-51-like (20.8%), ISAba1-blaOXA-23 (20.2%), and IS1006/IS1008-blaOXA-58 (11.6%). MBL genes, blaVIM-11,blaIMP-1, and blaIMP-19 were detected in 9 (5.2%), 20 (11.6%), and 1 (0.6%) CNSA isolates, respectively. Transfer of MBL genes to AB218 and AN254 recipient cells was successful for 7 and 6 of the 30 MBL-plasmids, respectively. The seven AB218-derived transconjugants carrying MBL-plasmids produced less biofilm but showed higher virulence to larvae than recipient AB218. CONCLUSIONS: Our 19-year longitudinal study revealed a stable increase in CNSA during 2005-2015. blaOXA-24-like, ISAba1-blaOXA-51-like, and ISAba1-blaOXA-23 were the major determinants of Acinetobacter carbapenem resistance. MBL-carrying plasmids contribute not only to the carbapenem resistance but also to A. baumannii virulence.

Minimum inhibitory concentrations of antifungals against invasive isolates of Cryptococcus species worldwide: Global antifungal antimicrobial testing leadership and surveillance program, 2010-2020.

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.

Sex-specific associations in multiparametric 3 T MRI measurements in adult livers.

BACKGROUND: MRI relaxometry mapping and proton density fat fraction (PDFF) have been proposed for the evaluation of hepatic fibrosis. However, sex-specific relationships of age and body fat with these MRI parameters have not been studied in detail among adults without clinically manifest hepatic disease. We aimed to determine the sex-specific correlation of multiparametric MRI parameters with age and body fat and to evaluate their interplay associations. METHODS: 147 study participants (84 women, mean age 48±14 years, range 19-85 years) were prospectively enrolled. 3 T MRI including T1, T2 and T1ρ mapping and PDFF and R2* map were acquired. Visceral and subcutaneous fat were measured on the fat images from Dixon water-fat separation sequence. RESULTS: All MRI parameters demonstrated sex difference except for T1ρ. PDFF was more related to visceral than subcutaneous fat. Per 100 ml gain of visceral or subcutaneous fat is associated with 1 or 0.4% accretion of liver fat, respectively. PDFF and R2* were higher in men (both P = 0.01) while T1 and T2 were higher in women (both P < 0.01). R2* was positively but T1 and T2 were negatively associated with age in women (all P < 0.01), while T1ρ was positively related to age in men (P < 0.05). In all studies, R2* was positively and T1ρ was negatively associated with PDFF (both P <0.0001). CONCLUSION: Visceral fat plays an essential role in the elevated liver fat. When using MRI parametric measures for liver disease evaluation, the interplay between these parameters should be considered.

The mechanisms of arterial signal intensity profile in non-contrast coronary MRA (NC-MRCA): a 3D printed phantom investigation and clinical translations.

Signal intensity (SI) drop has been proposed as an indirect stenosis assessment in non-contrast coronary MRA (NC-MRCA) but it uses unproven assumptions. We aimed to clarify the mechanisms that govern the SI in vitro and develop a stenosis detection method in vivo. Flow phantom tubes with/without stenosis were scanned under two spatial resolutions (0.5/1.0 mm3) on a 3.0 T MRI. Thirty-two coronary arteries from 11 volunteers were prospectively scanned with an EKG- and respiratory-gated 3D NC-MRCA with a resolution of 1.0 mm3, with coronary computed tomography angiography (CTA) as reference. The normalized SI along the centerline of the tubes or the coronary arteries was assessed against the distance from the orifice using a linear regression model. Its coefficient (SI decay slope) and goodness-of-fit (R2) were extracted to assess the effect of flow velocity and stenosis on the SI profile curve. The R2 was utilized for the stenosis detection. Phantom study: A slow flow velocity caused a steep SI decay slope. The SI drop revealed only at the inlet and outlet of stenosis due to the flow turbulence/vortex and yielded low R2, in which shape changed by the resolution. Clinical study: The R2 cutoff to detect ≥ 50% stenosis for the left and right coronary arteries were 0.64 and 0.20 with a sensitivity/specificity of 71.5/71.5 and 66.7/100 (%), respectively. The SI drop did not reflect the actual stenosis position and not suitable for the stenosis localization. The R2 cutoff represents an alternative method to detect stenoses on NC-MRCA at vessel level.Trial registration: ClinicalTrials.gov; NCT03768999, registered on December 7, 2018.

Optimal lifestyle behaviors and 10-year progression of arterial stiffness: The Multi-Ethnic Study of Atherosclerosis.

Majority of previous studies showed no association between a single health behavior and arterial stiffness, but the benefit of simultaneously having multiple healthy behaviors (optimal lifestyle) on the progression of arterial stiffness is unknown. Among 2810 individuals (age 60.0 ± 9.4, 46.5% male), optimal lifestyle marker (yes/no) on four health behaviors (ie, BMI < 25 kg/m2 , never or former smoker, never or moderate drinker, exercised > 500 METS min/week) across four visits (≈ 5 years) were summed to create an optimal lifestyle score. Carotid arterial stiffness was measured using distensibility coefficient (DC) and Young's elastic modulus (YEM) at visit 1 and after a mean of 9.5 years (visit 5). The association of optimal lifestyle with 10-year percent change in DC and YEM was assessed using multiple linear regression. DC decreased by 5.3% and YEM increased by 24.4% over 10 years. Mean optimal lifestyle score was 9.4 ± 3.1 (range: 0-16). Individuals in quintiles 2-5 of optimal lifestyle score compared to quintile 1 (with the least optimal lifestyle score) did not show slower deceleration of DC [Q2, -0.3% (95% CI: -6.0, 5.4); Q3, -0.01% (-4.5, 4.5); Q4, -0.6% (-5.2, 3.9); Q5, -0.4% (-5.3, 4.4)], trend p-value = .82] or slower progression of YEM [Q2, 0.1% (-7.1, 7.3); Q3, -0.8% (-8.0, 6.5); Q4, 4.5% (-2.3, 11.3); Q5, -0.2% (-8.3, 7.9)], trend p-value = .49] after adjusting for risk factors. The association remained non-significant when stratified by categories of age, sex, race, BP control, and diabetes. Our findings indicate that optimal score on multiple health behaviors may not independently slow arterial stiffness progression.

Myocardial fibrosis by T1 mapping magnetic resonance imaging predicts incident cardiovascular events and all-cause mortality: the Multi-Ethnic Study of Atherosclerosis.

AIMS: To evaluate whether myocardial fibrosis predicts cardiovascular events (CVEs) and mortality in the Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS: Cardiac magnetic resonance (CMR) T1 mapping with gadolinium administration for assessment of extracellular volume fraction (ECV) was performed in 1326 participants, in whom myocardial scar was assessed by late gadolinium enhancement (LGE). The clinical outcomes were defined as all-cause mortality, atherosclerotic CVEs, and incident heart failure (HF) during an average of 8 years of follow-up after the scan. Participants' mean native T1 time was 971 ms [standard deviation (SD) 45.5], ECV was 27 (SD 2.9), and 117 (8.8%) of them had LGE. At the time of the CMR exam, participant age was 68 years (SD 9) and 48% of them were women. Ideal cut-offs were identified using classification and regression trees accounting for time-to-event outcomes for ECV (30%) and native T1 time (954 ms). Over the follow-up period, 106 participants died, 78 developed CVE, and 23 developed HF. After adjustment for risk factors, ECV >30% was associated with death [hazard ratio (HR): 1.67, P < 0.05], incident CVE (HR: 2.02, P < 0.05), and incident HF (HR: 2.85, P < 0.05). After adjustments, native T1 >954 ms was associated with incident CVE (HR: 2.09, P < 0.05). Myocardial scar by LGE was not predictive of clinical outcomes after adjustments. CONCLUSION: ECV is an independent prognostic marker of incident HF, atherosclerotic CVEs, and all-cause mortality. ECV, with its ability to characterize both diffuse and focal fibrosis processes, better predicted incident events than regional myocardial abnormalities as visualized by LGE imaging in a large multi-ethnic population.

Whole-Exome Sequencing Identifies Genetic Variants for Severe Adolescent Idiopathic Scoliosis in a Taiwanese Population.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal curvature deformity that appears in the adolescent period. In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb's angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN, CLCN1, and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN, CLCN1, and SOX8 as the most likely susceptibility genes for severe AIS.

Evaluation of liver T1 using MOLLI gradient echo readout under the influence of fat.

BACKGROUND: The effect of hepatic steatosis on the gradient-echo (GRE) based Modified Look-Locker Inversion Recovery (MOLLI) technique for T1 mapping has not been evaluated. The purpose of this study was to evaluate a GRE based MOLLI technique for hepatic T1 mapping and determine the relationship of T1 differences (ΔT1) on in-phase (IP) and out-of-phase (OP) to fat fraction (FF) measurement. MATERIALS AND METHODS: 3 T MRI included MOLLI T1 mapping with TE = 1.3 (OP), 2.4 (IP), and 1.8 ms, and chemical-shift-encoded sequence with spectral modeling of fat to generate FF map as a reference. Bloch simulations and oil/water phantoms were used to characterize the response of the MOLLI T1 in various FF < 30% since MOLLI T1 estimation was erratic beyond this limit. Curve fit between ΔT1 and FF from simulation was applied to validate the phantom and the in-vivo results. Thirty-eight normal volunteers were included (16 women, Age 44 ± 12 years, BMI 27 ± 5.3 kg/m2). MOLLI water images were reconstructed by the average of OP and IP images, and the T1 values on water images served as the reference for T1 bias calculation defined as the percent difference between OP, IP, TE = 1.8 ms and the referenced water T1. Linear regression was performed to correlate the FF quantified by the reference and MOLLI methods. RESULTS: Phantom results were consistent with the Bloch simulations. The simulated relationship between FF (0-30%) and ΔT1 could be modeled precisely by a cubic equation with R2 = 1. In-vivo MOLLI ΔT1 and estimated FF were correlated to the reference FF (both R2 ≥ 0.96 and P < 0.001). TE = 1.8 ms demonstrated less T1 bias (-1.34%) compared to TE = OP (5.32%) or IP (-3.8%, both P < 0.001). CONCLUSION: At 3 T, TE of 1.8 ms can be used to reduce the T1 bias and deliver consistent T1 values when FF is <30%.

Effectiveness of hepatitis A vaccination among people living with HIV in Taiwan: Is one dose enough?

BACKGROUND: Single dose hepatitis A virus (HAV) vaccine had been proven its efficacy in immunocompetent but not immunocompromised hosts. We aim to investigate the effectiveness of one dose versus 2 doses HAV vaccine among people living with HIV (PLHIV). METHOD: We conducted a 1:1 single center retrospective case-control study for PLHIV in Northern Taiwan. Case patients were those who received single dose HAV vaccine and controls were those who completed standard 2 doses HAV vaccine. Nationwide campaign of single dose HAV vaccine had been practiced for high risk population including PLHIV and those who had newly diagnosed sexually transmitted diseases. RESULTS: During February 2016 and December 2017, 90 cases received single dose HAV vaccine provided while the other 90 age-matched controls received 2 doses vaccine were enrolled. We found more injection drug users (22.22% vs. 1.11%, p < 0.0001), more co-infection with viral hepatitis C (28.89% vs. 5.56%, p < 0.0001), and history of syphilis infection (56.67% VS 30%, p = 0.0003) in single dose group than 2 doses group. Seroconversion rate at one year was significantly higher in 2 doses group (97.78% vs 56.67%, p < 0.0001). Among single dose group, people with hepatitis B or C virus co-infection (HBV: p = 0.02, aOR: 0.03, 95% CI: 0.002-0.55; HCV: p = 0.002, aOR: 0.22, 95% CI: 0.08-0.58) were less likely to achieve seropositivity, while those who had higher CD4 count at baseline and one year, had better response to vaccine. CONCLUSION: Two doses HAV vaccine is necessary among PLHIV to achieve sustained seroresponse rather than single dose.

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.

Ryanodine Receptor 1-Related Myopathies: Quantification of Intramuscular Fatty Infiltration from T1-Weighted MRI.

BACKGROUND: Ryanodine receptor 1-related myopathy (RYR1-RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI). OBJECTIVE: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1-RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity. METHODS: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences. A modified ImageJ-based program was used for quantification. IMFI data was analyzed by mode of inheritance, motor function, and clinical severity. RESULTS: Upper and lower leg IMFI from 36 genetically confirmed and ambulatory RYR1-RM affected individuals (26 dominant and 10 recessive) were analyzed using Grey-scale quantification. There was no statistically significant difference in IMFI between dominant and recessive cases in upper or lower legs. IMFI in both upper and lower legs was inversely correlated with participant performance on the motor function measure (MFM-32) total score (upper leg: p < 0.001; lower leg: p = 0.003) and the six-minute walk test (6MWT) distance (upper leg: p < 0.001; lower leg: p = 0.010). There was no significant difference in mean IMFI between participants with mild versus severe clinical phenotypes (p = 0.257). CONCLUSION: A modified ImageJ-based algorithm was able to select and quantify fatty infiltration in a cohort of heterogeneously affected individuals with RYR1-RM. IMFI was not predictive of mode of inheritance but showed strong correlation with motor function and capacity tests including MFM-32 and 6MWT, respectively.

Automated workflow for volumetric assessment of signal intensity ratio on T1-weighted MR images after multiple gadolinium administrations.

Purpose: Repeated injections of linear gadolinium-based contrast agent (GBCA) have shown correlations with increased signal intensities (SI) on unenhanced T1-weighted (T1w) images. Assessment is usually performed manually on a single slice and the SI as an average of a freehand region-of-interest is reported. We aim to develop a fully automated software that segments and computes SI ratio of dentate nucleus (DN) to pons (DN/P) and globus pallidus (GP) to thalamus (GP/T) for the assessment of gadolinium presence in the brain after a serial GBCA administrations. Approach: All patients ( N = 113 ) underwent at least eight GBCA enhanced scans. The modal SI in the DN, GP, pons, and thalamus were measured volumetrically on unenhanced T1w images and corrected based on the reference protocol (measurement 1) and compared to the SI-uncorrected-modal-volume (measurement 2), SI-corrected-mean-volume (measurement 3), as well as SI-corrected-modal-single slice (measurement 4) approaches. Results: Automatic processing worked on all 2119 studies (1150 at 1.5 T and 969 at 3 T). DN/P were 1.085 ± 0.048 (1.5 T) and 0.979 ± 0.061 (3 T). GP/T were 1.084 ± 0.039 (1.5 T) and 1.069 ± 0.042 (3 T). Modal DN/P ratios from volumetric assessment at 1.5 T failed to show a statistical difference with or without SI corrections ( p = 0.71 ). All other t -tests demonstrated significant differences (measurement 2, 3, 4 compared to 1, p < 0.001 ). Conclusion: The fully automatic method is an effective powerful tool to streamline the analysis of SI ratios in the deep brain tissues. Divergent SI ratios using different approaches reinforces the need to standardize the measurement for the research in this field.

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.

Clinical Experience of Patients With Hepatitis C Treated With Direct-Acting Antivirals After Heart Transplantation.

BACKGROUND: Hepatitis C increases the mortality and morbidity of patients after heart transplant. Direct-acting antivirals (DAAs) are the primary drugs for hepatitis C treatment. However, such drugs are expensive and frequently unaffordable for patients. In DAA treatment, the assessment of drug interaction is crucial. METHODS: We investigated a retrospective case series study from January 2017 to December 2019. Sustained virologic response 12 (SVR12) was used to assess the effectiveness of DAA treatment. Data on patients' demographic information, timing of hepatitis C virus (HCV) infection (before or after heart transplant), HCV genotypes and viral loads, DAAs used (branded drugs or generic drugs), and drug interaction assessments were collected. RESULTS: Fifteen heart transplant patients received hepatitis C treatments during the study period, 11 of whom were infected because their donors had hepatitis C. After DAA treatment, HCV was undetectable in all patients, and 93.3% of them achieved SVR12. Nine patients used the generic sofosbuvir/velpatasvir, and 88.9% of them achieved SVR12. A total of 256 drugs were used with DAAs; 51 records of drug interactions were noted, 3 of which were contraindications, and the remaining records were potential interactions. Patients who used sofosbuvir or elbasvir/grazoprevir experienced fewer drug interactions. CONCLUSIONS: DAA treatment is effective for hepatitis C treatment in patients after heart transplant. Patients who cannot afford branded drugs because of their prices can use generic drugs as an alternative. Drug interactions must be surveyed during DAA treatment.

Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy.

OBJECTIVE: To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS). METHODS: Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes. RESULTS: The cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages. CONCLUSION: MRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy. CLINICALTRIALSGOV IDENTIFIER: NCT01417533.

Brief Report: Adiponectin Levels Linked to Subclinical Myocardial Fibrosis in HIV.

BACKGROUND: Persons living with HIV (PLWH) are at an increased risk of myocardial dysfunction and metabolic disturbances represent one of several potential contributing factors. Adiponectin is an adipokine that enhances insulin sensitivity with potential cardioprotective effects. We therefore investigated the relationship between myocardial fibrosis, adiponectin, and related metabolic parameters to better understand the pathophysiologic mechanisms of myocardial injury in PLWH. METHODS: This is a prospective, cross-sectional study of PLWH without known cardiovascular disease (n = 87) and 28 healthy matched controls. Diffuse myocardial fibrosis and epicardial adipose tissue (EAT) were evaluated using cardiac magnetic resonance imaging and cardiac computed tomography. RESULTS: Myocardial fibrosis was increased in PLWH and was correlated with adiponectin (r = 0.26, P = 0.004) and EAT (r = -0.42, P < 0.0001). Myocardial fibrosis was not associated with smoking pack years or CD4/CD8 ratio. In multivariate analysis that included body mass index, HIV status (P = 0.04), female sex (P < 0.0001), higher adiponectin (P = 0.046) and lower EAT (P = 0.01) were independently associated with myocardial fibrosis. CONCLUSION: We describe a novel association between serum adiponectin and subclinical intramyocardial fibrosis, as well as a significant inverse relationship between intramyocardial fibrosis and EAT. Adiponectin may represent a target for preventing myocardial injury in the future; however, our findings reflect the complexity of the metabolic interactions of adiponectin and epicardial adipose as factors associated with the myocardial architecture.

Vitamin E sequestration by liver fat in humans.

BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.