Kupffer cell pyroptosis mediated by METTL3 contributes to the progression of alcoholic steatohepatitis.

Chronic alcohol consumption is a major risk factor for alcoholic steatohepatitis (ASH). Previous studies have shown that direct injury of hepatocytes is the key factor in its occurrence and development. However, our study shows that the role of Kupffer cells in ASH cannot be ignored. We isolated Kupffer cells from the livers of ASH mice and found that alcohol consumption induced Kupffer cell pyroptosis and increased the release of interleukin-1ß (IL-1ß). Furthermore, we screened the related m6A enzyme methyltransferase-like 3 (METTL3) from liver Kupffer cells, and found that silencing METTL3 alleviated inflammatory cytokine eruption by Kupffer cell pyroptosis in ASH mice. In vitro, we silenced METTL3 with lentivirus in BMDMs and RAW264.7 cells and confirmed that METTL3 could reduce pyroptosis by influencing the splicing of pri-miR-34A. Together, our results revealed a critical role of KC pyroptosis in ASH and highlighted the mechanism by which METLL3 relieves cell pyroptosis, which could be a promising therapeutic strategy for ASH.

Consistency of Monoenergetic Attenuation Measurements for a Clinical Dual-Source Photon-Counting Detector CT System Across Scanning Paradigms: A Phantom Study.

BACKGROUND. Use of virtual monoenergetic images (VMIs) from multienergy CT scans can mitigate inconsistencies in traditional attenuation measurements that result from variation in scan-related factors. Photon-counting detector (PCD) CT systems produce VMIs as standard image output under flexible scanning conditions. OBJECTIVE. The purpose of this article was to evaluate the consistency of monoenergetic attenuation measurements obtained from a clinical PCD CT scanner across a spectrum of scanning paradigms. METHODS. A phantom with 10 tissue-simulating inserts was imaged using a clinical dual-source PCD CT scanner. Nine scanning paradigms were obtained across combinations of tube voltages (90, 120, and 140 kVp) and image quality (IQ) levels (80, 145, and 180). Images were reconstructed at VMI levels of 50, 60, 70, and 80 keV. Consistency of attenuation measurements was assessed, using the 120 kVp with IQ level of 145 scanning paradigm as the reference scan. RESULTS. For all scanning paradigms, attenuation measurements showed intra-class correlation of 0.999 and higher with respect to the reference scan. Across inserts, mean bias relative to the reference scan ranged from -14.9 to 13.6 HU, -2.7 to 1.7 HU, and -3.9 to 3.8 HU at tube voltages of 90, 120, and 140 kVp, respectively; and from -14.9 to 13.6 HU, -6.4 to 3.8 HU, -3.7 to 1.4 HU, and -7.2 to 4.3 HU at VMI levels of 50, 60, 70, and 80 keV, respectively. Thus, mean bias did not exceed 5 HU for any insert at tube potentials of 120 kVp and 140 kVp, nor for any insert at a VMI level of 70 keV. At a VMI level of 50 keV and tube potential of 90 kVp, mean bias exceeded 5 HU for 14 of 30 possible combinations of inserts and scanning paradigms and exceeded 10 HU for four of 30 such combinations. At VMI levels of both 60 and 80 keV, mean bias exceeded 5 HU for only two combinations of inserts and scanning paradigms, all at a tube potential of 90 kVp. CONCLUSION. PCD CT generally provided consistent attenuation measurements across combinations of scanning paradigms and VMI levels. CLINICAL IMPACT. PCD CT may facilitate quantitative applications of CT data in clinical practice.

Ecological and functional differences of abundant and rare sub-communities in wastewater treatment plants across China.

The microbial community in activated sludge is composed of a small number of abundant sub-community with high abundance and a large number of rare sub-community with limited abundance. Our knowledge regarding the ecological properties of both abundant and rare sub-communities in activated sludge is limited. This article presented an analysis of functional prediction, assembly mechanisms, and biogeographic distribution characteristics of abundant and rare sub-communities in 211 activated sludge samples from 60 wastewater treatment plants across China. Moreover, this study investigated the dominant factors influencing the community structure of these two microbial groups. The results showed that the functions associated with carbon and nitrogen cycling were primarily detected in abundant sub-community, while rare sub-community were primarily involved in sulfur cycling. Both microbial groups were mainly influenced by dispersal limitation, which, to some extent, resulted in a distance-decay relationship in their biogeographic distribution. Moreover, a higher spatial turnover rate of rare sub-communities (0.0887) suggested that spatial differences in microbial community structure among different WWTPs may mainly result from rare sub-community. Moreover, SEM showed that geographic locations affected rare sub-communities greatly, which agreed with their higher dispersal limitation and turnover rate. In contrast, influent characteristics showed stronger correlations with abundant sub-communities, suggesting that abundant sub-community may contribute more to the removal of pollutants. This study enhanced our understanding of abundant and rare microorganisms in activated sludge especially the role of rare species and provided scientific evidence for precise regulation and control of wastewater treatment plants.

Age-Related Changes in the Spatial Variation of Magnetic Susceptibility of Human Articular Cartilage.

BACKGROUND: Quantitative susceptibility mapping (QSM) has shown great potential for revealing the layer structure of articular cartilage based on the laminar susceptibility difference at different depths. However, more information is needed on the effects of age on the spatial distribution of magnetic susceptibility in human cartilage. PURPOSE: To assess the ability of QSM to quantify the age-related differences in depth-wise cartilage susceptibility values in healthy populations. STUDY TYPE: Prospective. POPULATION: A total of 94 healthy asymptomatic subjects in three age cohorts: 19-30 (n = 36, 20 males), 31-50 (n = 45, 27 males), and 51-66 years (n = 13, 7 males). FIELD STRENGTH/SEQUENCE: 3D gradient echo sequences at 3.0 T. ASSESSMENT: Four cartilage compartments were analyzed, including the central lateral/medial femur (cLF/cMF) and the lateral/medial tibia (LT/MT). The spatial susceptibility profile and the corresponding 95% confidence interval (CI) of each age cohort were obtained as functions of the normalized distance from the bone-cartilage interface to the cartilage surface (cartilage depth from 0.0 to 1.0). STATISTICAL TESTS: The relationship between age and cartilage thickness of each cartilage subregion was tested by Pearson correlation with P < 0.05 considered significant. Cartilage depths with separations of 95% CIs were considered to have significant susceptibility differences between two age cohorts with a Bonferroni-corrected P < 0.05. RESULTS: The cartilage thickness did not change significantly with age (P value range: 0.06-0.85). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 31-50-year-olds in the deep layer of cMF (cartilage depth: 0.0-0.22) and LT (0.05-0.28). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 19-30-year-olds near the cartilage-bone interface of cMF (0.0-0.34), cLF (0.0-0.28), and LT (0.0-0.58). There were also significantly higher susceptibilities in the 31-50-year-olds compared with the 19-30-year-olds in the deeper regions of cMF (0.26-0.57), cLF (0.0-0.40), and LT (0.07-0.80). DATA CONCLUSION: Age-related susceptibility changes in the deeper regions of knee cartilage were observed using QSM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The role of the core microorganisms in the microbial interactions in activated sludge.

In order to gain a deeper understanding of the microbial interactions in wastewater treatment plants (WWTPs) in China and clarify the role of the core community in the microbial interactions in activated sludge (AS), this study used a molecular ecological network approach based on random matrix theory to construct co-occurrence networks of the core microorganisms (CoreN), the whole AS community (WholeN) and the microbial communities without the core microorganisms (OtherN), respectively. It was shown that the WholeN had more complex and tighter connections compared with the OtherN, because of its higher total number of nodes, higher average clustering coefficient, and shorter average geodesic distance. The proportions of positive links in the CoreN, WholeN and OtherN were gradually decreased, indicating that the core microorganisms promoted cooperation between AS microorganisms. Moreover, higher robustness after random removal of 50% of the nodes of the WholeN (0.2836 ± 0.0311) was observed than the robustness of the OtherN (0.1152 ± 0.0263). In addition, the vulnerability of OtherN (0.0514) is significantly higher than WholeN (0.0225). Meanwhile, the average ratio of negative/positive cohesion, was significantly decreased when the core microorganisms were removed. These results demonstrated that core community could strengthen the stability of the ecological network in AS. By discerning the key factors affecting ecological network, AS temperature was observed to have a strong correlation with all three networks. Moreover, pollutants in wastewater shown stronger correlations with the CoreN and WholeN, supporting the point that core community play a critical role in pollutant removal in WWTPs to a certain extent.

A virtual simulation-based training program on birthing positions: a randomized controlled trial.

BACKGROUND: Restricting parturient women in healthcare facilities from choosing positions that provide the greatest comfort and benefit during labor is a global barrier. Several complex factors, including caregiver preference and medical intervention, shape the limitation. Therefore, a practical need exists to train midwives on the knowledge and skills to change this condition. METHODS: The study used a parallel, single-blind, randomized controlled trial at a provincial maternity and child health hospital in Fujian, China, from June 1 to December 31, 2019. The midwives in a birth suite were selected and randomly enrolled in a one-month simulation-based hybrid training or face-to-face teaching in September 2019. The four-level Kirkpatrick's model, including reaction, learning, behavior, and results, was used to evaluate training effects before and after the program. Data were analyzed with SPSS 25.0 using Student's t-test, Spearman's correlation test, Mann-Whitney U test, Wilcoxon signed-rank test, and chi-square test analysis of variance. The significance level was set at p < 0.05. RESULTS: Forty-two midwives were initially randomized to either the virtual simulation group or the face-to-face group. One midwife was excluded from the analysis due to intervention discontinuation, resulting in a final analysis of 41 midwives (n1 = 21, n2 = 20). Post-intervention, the virtual simulation group exhibited higher satisfaction and learning effects compared to the face-to-face group, while the rate of perineal incision in primiparas was lower (p<0.05). No significant changes or differences were observed in self-rated behavior between the two groups (p>0.05). The virtual simulation group demonstrated an increase in non-supine birth rate (p = 0.030) and a decrease in perineal incision rate among primiparas compared to pre-intervention (p = 0.035). Moreover, knowledge performance was associated with the duration of virtual simulation (r = 0.664, p = 0.001). CONCLUSIONS: Virtual simulation is a fascinating innovation that enables midwives to develop birthing positions without practicing on real pregnant women and is one solution to achieve work competency within a shortened training period.

Exact simultaneous confidence intervals for logical selection of a biomarker cut-point.

This article proposes four new principles for logical biomarker cut-point selection methods to adhere to: subgroup sensibility, sensitivity, specificity, and target monotonicity. At every cut-point value, our method gives confidence intervals not only for the efficacy at that cut-point value, but also efficacies in the marker-positive and marker-negative subgroups defined by that cut-point. These confidence intervals are given simultaneously for all possible cut-point values. Using Alzheimer's disease (AD) and type 2 diabetes (T2DM) as examples, we show our method achieves the four principles. Our method strongly controls familywise type I error rate (FWER) across both levels of multiplicity: the multiplicity of having marker-positive and marker-negative subgroups at each cut-point, and the multiplicity of searching through infinitely many cut-points. This is in contrast to other available methods. The confidence level of our simultaneous confidence intervals is in fact exact (not conservative). An application (app) is available, which implements the method we propose.

Whole-liver histogram and texture analysis on T1 maps improves the risk stratification of advanced fibrosis in NAFLD.

OBJECTIVES: To assess whole-liver texture analysis on T1 maps for risk stratification of advanced fibrosis in patients with suspected nonalcoholic fatty liver disease (NAFLD). METHODS: This retrospective study included 53 patients. Histogram and texture parameters (volume, mean, SD, median, 5th percentile, 95th percentile, skewness, kurtosis, diff-entropy, diff-variance, contrast, and entropy) of T1 maps were calculated based on the semi-automatically segmented whole-liver volume. A two-step approach combining the Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) and Fibrosis-4 Index (FIB-4) with the liver stiffness measurement (LSM) for the risk stratification was used. Univariate analysis was performed to identify significant parameters. Logistic regression models were then run on the significant features. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis. RESULTS: In total, 33 (62%) subjects had a low risk and 20 (38%) subjects had an intermediate-to-high risk of advanced fibrosis. The following significantly different parameters with the best performance were diff-entropy, entropy, and diff-variance, with AUROC 0.837 (95% CI 0.73-0.95), 0.821 (95% CI 0.71-0.94), and 0.807 (95% CI 0.69-0.93). The optimal combination of median, 5th percentile, and diff-entropy as a multivariate model improved the diagnostic performance to diagnose an intermediate-to-high risk of advanced fibrosis with AUROC 0.902(95% CI 0.79-0.97). CONCLUSIONS: Parameters obtained by histogram and texture analysis of T1 maps may be a noninvasive analytical approach for stratifying the risk of advanced fibrosis in NAFLD. KEY POINTS: • Variable flip angle (VFA) T1 mapping can be used to acquire 3D T1 maps within a clinically acceptable duration. • Whole-liver histogram and texture parameters on T1 maps in patients with NAFLD can distinguish those with an intermediate-to-high risk of advanced fibrosis. • The multivariate model of combination of texture parameters improved the diagnostic performance for a high risk of advanced fibrosis and clinical parameters offer no added value to the multivariate model.

Myopic Retinal Changes Screening: Comparison of Sensitivity and Specificity among 15 Combinations of Ultrawide Field Scanning Laser Ophthalmoscopy Images.

AIM: The objective of the study was to investigate the evaluation indices (diagnostic test accuracy and agreement) of 15 combinations of ultrawide field scanning laser ophthalmoscopy (UWF SLO) images in myopic retinal changes (MRC) screening to determine the combination of imaging that yields the highest evaluation indices in screening MRC. METHODS: This is a retrospective study of UWF SLO images obtained from myopes and were analyzed by 2 retinal specialists independently. Five field UWF SLO images that included the posterior (B), superior (S), inferior (I), nasal (N), and temporal (T) regions were obtained for analysis and its results used as a reference standard. The evaluation indices of different combinations comprising 1 to 4 fields of the retina were compared to determine the abilities of each combination screens for MRC. RESULTS: UWF SLO images obtained from 823 myopic patients (1,646 eyes) were included for the study. Sensitivities ranged from 50.0 to 98.9% (95% confidence interval (CI), 43.8-99.7%); the combinations of B + S + I (97.3%; 95% CI, 94.4-98.8%), B + T + S + I (98.5%; 95% CI, 95.9-99.5%), and B + S + N + I (98.9%; 95% CI, 96.4-99.7%) ranked highest. Furthermore, the combinations of B + S + I, B + T + S + I, and B + S + N + I also revealed the highest accuracy (97.7%; 95% CI, 95.1-100.0, 98.6; 95% CI, 96.7-100.0, 98.8; 95% CI, 96.9-100.0%) and agreement (kappa = 0.968, 0.980, and 0.980). For the various combinations, specificities were all higher than 99.5% (95% CI, 99.3-100.0%). CONCLUSIONS: In our study, screening combinations of B + S + I, B + T + S + I, and B + S + N + I stand out with high-performing optimal evaluation indices. However, when time is limited, B + S + I may be more applicable in primary screening of MRC.

Self-Amplification of Tumor Oxidative Stress with Degradable Metallic Complexes for Synergistic Cascade Tumor Therapy.

The ferroptosis effect has been illuminated with a clear Fenton reaction mechanism that converts endogenous hydrogen peroxide (H2O2) into highly oxidative hydroxyl radicals (·OH) in ROS-amplified tumor therapy. This ferroptosis-related oxidation effect was then further enhanced by the enzyme-like roles of cisplatin (CDDP). This CDDP-induced apoptosis was promoted in reverse by ferroptosis via the depletion of glutathione (GSH) and prevention of DNA damage repair. Here, we have developed degradable metallic complexes (PtH@FeP) containing an Fe(III)-polydopamine (FeP) core and HA-cross-linked CDDP (PtH) shell, exaggerating in situ toxic ROS production via the synergistic effect of CDDP and Fe(III). Taken together, the rationally designed PtH@FeP provided a new strategy for self-amplified synergistic chemotherapy/ferroptosis/photothermal therapy (PTT) antitumor effects with a reduced dosage that facilitates clinical safety.

MiR-1246 promotes anti-apoptotic effect of mini-αA in oxidative stress-induced apoptosis in retinal pigment epithelial cells.

BACKGROUND: Geographic atrophy (GA) is a late-stage symptom of an age-related macular degeneration (AMD), characterized by the loss of retinal pigment epithelial (RPE) cells and photoreceptor functions. Despite being a major cause of blindness in individuals of 65 years of age and older, some forms of AMD, including GA, still lack targeted treatment. Our previous study demonstrated that mini-αA peptide, which contains the functional site of αA-crystallin, protected RPE cells from NaIO3 -induced apoptosis. METHODS: To further investigate the underlying mechanism, we applied next-generation sequencing analysis to identify miR-1246 as a putative mediator of mini-αA protective function. To investigate the role of miR-1246 in RPE cell apoptosis, a stable miR-1246-low-expression cell line was established by using miR-1246 inhibitor. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to investigate the proliferation of RPE cells, mRNA and miR-1246 expression were detected by the quantitative reverse transcriptase-polymerase chain reaction. RESULTS: We have further identified caspase-3 and caspase-14 as molecular targets of miR-1246 involved in regulation of apoptosis in NaIO3 -incubated cells. Interestingly, disruption of miR-1246 expression enhanced anti-apoptotic effect of mini-αA on RPE cells during oxidative stress. CONCLUSIONS: Our results provide a mechanistic basis for evaluation of miR-1246 as a new candidate target for the clinical treatment of AMD.

Statistics for X-chromosome associations.

In a genome-wide association study (GWAS), association between genotype and phenotype at autosomal loci is generally tested by regression models. However, X-chromosome data are often excluded from published analyses of autosomes because of the difference between males and females in number of X chromosomes. Failure to analyze X-chromosome data at all is obviously less than ideal, and can lead to missed discoveries. Even when X-chromosome data are included, they are often analyzed with suboptimal statistics. Several mathematically sensible statistics for X-chromosome association have been proposed. The optimality of these statistics, however, is based on very specific simple genetic models. In addition, while previous simulation studies of these statistics have been informative, they have focused on single-marker tests and have not considered the types of error that occur even under the null hypothesis when the entire X chromosome is scanned. In this study, we comprehensively tested several X-chromosome association statistics using simulation studies that include the entire chromosome. We also considered a wide range of trait models for sex differences and phenotypic effects of X inactivation. We found that models that do not incorporate a sex effect can have large type I error in some cases. We also found that many of the best statistics perform well even when there are modest deviations, such as trait variance differences between the sexes or small sex differences in allele frequencies, from assumptions.

Quantitative susceptibility mapping of articular cartilage in patients with osteoarthritis at 3T.

BACKGROUND: Quantitative susceptibility mapping (QSM) has recently been applied in humans to quantify the magnetic susceptibility of collagen fibrils in the articular cartilage. PURPOSE: To determine the ability of QSM to detect cartilage matrix degeneration between normal and early knee osteoarthritis (OA) patients. STUDY TYPE: Prospective. POPULATION: Twenty-four patients with knee OA and 24 age- and sex-matched healthy controls. FIELD STRENGTH/SEQUENCE: 3D gradient echo, T1 turbo spin echo, and proton density-weighted (PDw) spectral attenuated inversion recovery (SPAIR) sequence at 3.0T. ASSESSMENT: Scan-rescan reproducibility of the susceptibility values in the cartilage was assessed in control subjects. Cartilage thickness, volume, mean, and standard deviation (SD) of susceptibility values of the cartilage compartments were compared between normal and OA patients. The relationship between magnetic susceptibility values and cartilage lesion grading based on MR images was studied. STATISTICAL TESTS: The Wilcoxon Rank-Sum test was used to compare cartilage thickness, volume, mean, and SD of susceptibility values between control subjects and OA patients. A Spearman rank correlation was performed to study the relationship between the mean and SD of susceptibility values and the cartilage thinning grades. RESULTS: The SD of magnetic susceptibility values in the knee cartilage was significantly lower in OA patients compared with healthy controls, and it decreased with more severe MR grades of cartilage thinning degeneration. Significant correlations between the SD of susceptibility values and cartilage thinning grades were observed with R2 = 0.64 and P = 0.000, R2 = 0.47 and P = 0.002, R2 = 0.52 and P = 0.001, R2 = 0.42 and P = 0.0006, and R2 = 0.67 and P = 0.000 for medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibia (MT), lateral tibia (LT), and patella, respectively. No significant difference was found in cartilage volume (P = 0.17, P = 0.13, P = 0.20, P = 0.25, and P = 0.18 for MFC, LFC, MT, LT, and patella, respectively) and thickness (P = 0.31, P = 0.19, P = 0.16, P = 0.09, and P = 0.22 for MFC, LFC, MT, LT, and patella, respectively) between OA patients and healthy controls. DATA CONCLUSION: The variations of susceptibility values in the knee cartilage decrease with the degree of cartilage degeneration. QSM may be a sensitive indicator for alteration of the collagen network and shows potential to detect cartilage degeneration at early stage. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

Correct and logical inference on efficacy in subgroups and their mixture for binary outcomes.

Targeted therapies are becoming more common. In targeted therapy development, suppose its companion diagnostic test divides patients into a marker-positive subgroup and its complementary marker-negative subgroup. To find the right patient population for the therapy to target, inference on efficacy in the marker-positive and marker-negative subgroups as well as efficacy in the overall mixture population are all of interest. Depending on the type of clinical endpoints, inference on mixture population can be nontrivial and commonly used efficacy measures may not be suitable for a mixture population. Correlations among estimates of efficacy in the marker-positive, marker-negative, and overall mixture population play a crucial role in using an earlier phase study to inform on the design of a confirmatory study (e.g., determination of sample size). This article first shows that when the clinical endpoint is binary (such as respond or not), odds ratio is inappropriate as an efficacy measure in this setting, but relative response (RR) is appropriate. We show a safe way of calculating estimated correlations is to consider mixing subgroup response probabilities within each treatment arm first, and then derive the joint distribution of RR estimates. We also show, if one calculates RR within each subgroup first, how wrong the correlations can be if the Delta method derivation fails to take randomness of estimating the mixing coefficient into account.

Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. METHODS: In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. FINDINGS: Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. INTERPRETATION: Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. FUNDING: Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Iron deposition quantification: Applications in the brain and liver.

Iron has long been implicated in many neurological and other organ diseases. It is known that over and above the normal increases in iron with age, in certain diseases there is an excessive iron accumulation in the brain and liver. MRI is a noninvasive means by which to image the various structures in the brain in three dimensions and quantify iron over the volume of the object of interest. The quantification of iron can provide information about the severity of iron-related diseases as well as quantify changes in iron for patient follow-up and treatment monitoring. This article provides an overview of current MRI-based methods for iron quantification, specifically for the brain and liver, including: signal intensity ratio, R2 , R2*, R2', phase, susceptibility weighted imaging and quantitative susceptibility mapping (QSM). Although there are numerous approaches to measuring iron, R2 and R2* are currently preferred methods in imaging the liver and QSM has become the preferred approach for imaging iron in the brain. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018. J. MAGN. RESON. IMAGING 2018;48:301-317.

Quantitative analysis of hepatic iron in patients suspected of coexisting iron overload and steatosis using multi-echo single-voxel magnetic resonance spectroscopy: Comparison with fat-saturated multi-echo gradient echo sequence.

BACKGROUND: The coexistence of hepatic iron and fat is common in patients with hyperferritinemia, which plays an interactive and aggressive role in the progression of diseases (fibrosis, cirrhosis, and hepatocellular carcinomas). PURPOSE: To evaluate a modified high-speed T2 -corrected multi-echo, single voxel spectroscopy sequence (HISTOV) for liver iron concentration (LIC) quantification in patients with hyperferritinemia, with simultaneous fat fraction (FF) estimation. STUDY TYPE: Retrospective cohort study. POPULATION: Thirty-eight patients with hyperferritinemia were enrolled. FIELD STRENGTH/SEQUENCE: HISTOV, a fat-saturated multi-echo gradient echo (GRE) sequence, and a spin echo sequence (FerriScan) were performed at 1.5T. ASSESSMENT: R2 of the water signal and FF were calculated with HISTOV, and R2* values were derived from the GRE sequence, with R2 and LIC from FerriScan serving as the references. STATISTICAL TESTS: Linear regression, correlation analyses, receiver operating characteristic analyses, and Bland-Altman analyses were conducted. RESULTS: Abnormal hepatic iron load was detected in 32/38 patients, of whom 10/32 had coexisting steatosis. Strong correlation was found between R2* and FerriScan-LIC (R2 = 0.861), and between HISTOV-R2_ water and FerriScan-R2 (R2 = 0.889). Furthermore, HISTOV-R2_ water was not correlated with HISTOV-FF. The area under the curve (AUC) for HISTOV-R2_ water was 0.974, 0.971, and 1, corresponding to clinical FerriScan-LIC thresholds of 1.8, 3.2, and 7.0 mg/g dw, respectively. No significant difference in the AUC was found between HISTOV-R2_ water and R2* at any of the LIC thresholds, with P-values of 0.42, 0.37, and 1, respectively. HISTOV-LIC showed excellent agreement with FerriScan-LIC, with a mean bias of 0.00 ± 1.18 mg/g dw, whereas the mean bias between GRE-LIC and FerriScan-LIC was 0.53 ± 1.49 mg/g dw. DATA CONCLUSION: HISTOV is useful for the quantification and grading of liver iron overload in patients with hyperferritinemia, particularly in cases with coexisting steatosis. HISTOV-LIC showed no systematic bias compared with FerriScan-LIC, making it a promising alternative for iron quantification. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018.

Quantitative susceptibility mapping (QSM) minimizes interference from cellular pathology in R2* estimation of liver iron concentration.

BACKGROUND: A challenge for R2 and R2* methods in measuring liver iron concentration (LIC) is that fibrosis, fat, and other hepatic cellular pathology contribute to R2 and R2* and interfere with LIC estimation. PURPOSE: To examine the interfering effects of fibrosis, fat, and other lesions on R2* LIC estimation and to use quantitative susceptibility mapping (QSM) to reduce these distortions. STUDY TYPE: Prospective. PHANTOMS, SUBJECTS: Water phantoms with various concentrations of gadolinium (Gd), collagen (Cl, modeling fibrosis), and fat; nine healthy controls with no known hepatic disease, nine patients with known or suspected hepatic iron overload, and nine patients with focal liver lesions. FIELD STRENGTH/SEQUENCE: The phantoms and human subjects were imaged using a 3D multiecho gradient-echo on clinical 1.5T and 3T MRI systems. ASSESSMENT: QSM and R2* images were postprocessed from the same gradient-echo data. Fat contributions to susceptibility and R2* were corrected in signal models for LIC estimation. STATISTICAL TESTS: Polynomial regression analyses were performed to examine relations among susceptibility, R2* and true [Gd] and [Cl] in phantoms, and among susceptibility and R2* in patient livers. RESULTS: In phantoms, R2* had a strong nonlinear dependency on [Cl], [fat], and [Gd], while susceptibility was linearly dependent (R2 > 0.98). In patients, R2* was highly sensitive to liver pathological changes, including fat, fibrosis, and tumors, while QSM was relatively insensitive to these abnormalities (P = 0.015). With moderate iron overload, liver susceptibility and R2* were not linearly correlated over a common R2* range [0, 100] sec-1 (P = 0.35). DATA CONCLUSION: R2* estimation of LIC is prone to substantial nonlinear interference from fat, fibrosis, and other lesions. QSM processing of the same gradient echo MRI data can effectively minimize the effects of cellular pathology. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1069-1079.

Quantitative susceptibility mapping in combination with water-fat separation for simultaneous liver iron and fat fraction quantification.

PURPOSES: To evaluate the feasibility of simultaneous quantification of liver iron concentration (LIC) and fat fraction (FF) using water-fat separation and quantitative susceptibility mapping (QSM). METHODS: Forty-five patients suspected of liver iron overload (LIO) were included. A volumetric interpolated breath-hold examination sequence for QSM and FF, a fat-saturated gradient echo sequence for R2*, a spin echo sequence for LIC measurements and MRS analyses for FF (FF-MRS) were performed. Magnetic susceptibility and FF were calculated using a water-fat separation method (FF-MRI). Correlation and receiver operating characteristic analyses were performed. RESULTS: Magnetic susceptibility showed strong correlation with LIC (rs=0.918). The optimal susceptibility cut-off values were 0.34, 0.63, 1.29 and 2.23 ppm corresponding to LIC thresholds of 1.8, 3.2, 7.0 and 15.0 mg/g dry weight. The area under the curve (AUC) were 0.948, 0.970, 1 and 1, respectively. No difference in AUC was found between susceptibility and R2* at all LIC thresholds. Correlation was found between FF-MRI and FF-MRS (R2=0.910). CONCLUSIONS: QSM has a high diagnostic performance for LIC quantification, similar to that of R2*. FF-MRI provides simultaneous fat quantification. Findings suggest QSM in combination with water-fat separation has potential value for evaluating LIO, especially in cases with coexisting steatosis. KEY POINTS: • Magnetic susceptibility showed strong correlation with LIC (r s =0.918). • QSM showed high diagnostic performance for LIC, similar to that of R 2* . • Simultaneously estimated FF-MRI showed strong correlation with MR-Spectroscopy-based FF (R 2 =0.910). • QSM combining water-fat separation has quantitative value for LIO with coexisted steatosis.