Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Inter-sonographer reproducibility of quantitative ultrasound outcomes and shear wave speed measured in the right lobe of the liver in adults with known or suspected non-alcoholic fatty liver disease.

ObjectivesTo assess inter-sonographer reproducibility of ultrasound attenuation coefficient (AC), backscatter coefficient (BSC) and shear wave speed (SWS) in adults with known/suspected non-alcoholic fatty liver disease (NAFLD).MethodsThe institutional review board approved this HIPAA-compliant prospective study; informed consent was obtained. Participants with known/suspected NAFLD were recruited and underwent same-day liver examinations with a clinical scanner. Each participant was scanned by two of the six trained sonographers. Each sonographer performed multiple data acquisitions in the right liver lobe using a lateral intercostal approach. A data acquisition was a single operator button press that recorded a B-mode image, radio-frequency data, and the SWS value. AC and BSC were calculated from the radio-frequency data using the reference phantom method. SWS was calculated automatically using product software. Intraclass correlation coefficient (ICC) and within-subject coefficient of variation (wCV) were calculated for applicable metrics.ResultsSixty-one participants were recruited. Inter-sonographer ICC was 0.86 (95% confidence interval: 0.77-0.92) for AC and 0.87 (0.78-0.92) for log-transformed BSC (logBSC = 10log10BSC) using one acquisition per sonographer. ICC was 0.88 (0.80-0.93) for both AC and logBSC averaging 5 acquisitions. ICC for SWS was 0.57 (0.29-0.74) using one acquisition per sonographer, and 0.84 (0.66-0.93) using 10 acquisitions. The wCV was ~7% for AC, and 19-43% for SWS, depending on number of acquisitions.ConclusionsHepatic AC, BSC and SWS measures on a clinical scanner have good inter-sonographer reproducibility in adults with known or suspected NAFLD. Multiple acquisitions are required for SWS but not AC or BSC to achieve good inter-sonographer reproducibility.Key points• AC, BSC and SWS measurements are reproducible in adults with NAFLD. • Inter-sonographer reproducibility of SWS measurement improves with more acquisitions being averaged. • Multiple acquisitions are required for SWS but not AC or BSC

Pharmaceutical assistance programs for cancer patients in the era of orally administered chemotherapeutics

Introduction: The rising cost of cancer drugs may make treatment unaffordable for some patients. Patients often rely on drug manufacturer-administered Pharmaceutical Assistance Programs (PAPs) to obtain drugs and reduced or no cost. The overall usage of PAPs within cancer care delivery is unknown. Methods: We included all cancer patients across an academically affiliated, integrated health system in North Carolina during 2014 (N = 8591). We identified the subset of patients receiving PAP assistance to afford one or more cancer drugs, in order to calculate the proportion of patients receiving PAP assistance, and the retail value of the assistance. Results: Among 8591 cancer patients, 215 unique patients submitted a total of 478 successful PAP requests for cancer drugs. 40% of PAP-utilizing patients were uninsured, 23% had Medicaid coverage, 20% had Medicare coverage, 2% were dual Medicare/Medicaid eligible, and 14% were commercially insured. Among all cancer patients who received medical treatment, 6.0% required PAP assistance, whereas 10.6% receiving an oral agent required PAP assistance. The proportion receiving PAP assistance varied substantially by drug, ranging from <1% of patients (e.g. carboplatin, methotrexate) to 50% of patients (e.g. ponatinib, temsirolimus). The majority of the retail value obtained was for oral agents, including $1,556,575 of imatinib and$1,449,633 of dasatinib, which were the two drugs with the highest aggregate retail value. Conclusions: A substantial proportion of cancer patients receive private charitable assistance to obtain standard-of-care treatments. This includes patients with federal and private insurance, suggesting an inability of patients to meet cost-sharing requirements

Liver fat imaging-a clinical overview of ultrasound, CT, and MR imaging.

Hepatic steatosis is a frequently encountered imaging finding that may indicate chronic liver disease, the most common of which is non-alcoholic fatty liver disease. Non-alcoholic&nbsp;fatty liver disease is implicated in the development of systemic diseases and its progressive phenotype, non-alcoholic steatohepatitis, leads to increased liver-specific morbidity and mortality. With the rising obesity epidemic and advent of novel therapeutics aimed at altering metabolism, there is a growing need to quantify and monitor liver steatosis. Imaging methods for assessing steatosis range from simple and qualitative to complex and highly accurate metrics. Ultrasound may be appropriate in some clinical instances as a screening modality to identify the presence of abnormal liver morphology. However, it lacks sufficient specificity and sensitivity to constitute a diagnostic modality for instigating and monitoring therapy. Newer ultrasound techniques such as quantitative ultrasound show promise in turning qualitative assessment of steatosis on conventional ultrasound into quantitative measurements. Conventional unenhanced CT is capable of detecting and quantifying moderate to severe steatosis but is inaccurate at diagnosing mild steatosis and involves the use of radiation. Newer CT techniques, like dual&nbsp;energy CT, show potential in expanding the role of CT in quantifying steatosis. MRI proton-density fat fraction is currently the most accurate and precise imaging biomarker to quantify liver steatosis. As such, proton-density fat fraction is the most appropriate noninvasive end&nbsp;point for steatosis reduction in clinical trials and therapy response assessment

Inter-sonographer reproducibility of quantitative ultrasound outcomes and shear wave speed measured in the right lobe of the liver in adults with known or suspected non-alcoholic fatty liver disease.

ObjectivesTo assess inter-sonographer reproducibility of ultrasound attenuation coefficient (AC), backscatter coefficient (BSC) and shear wave speed (SWS) in adults with known/suspected non-alcoholic fatty liver disease (NAFLD).MethodsThe institutional review board approved this HIPAA-compliant prospective study; informed consent was obtained. Participants with known/suspected NAFLD were recruited and underwent same-day liver examinations with a clinical scanner. Each participant was scanned by two of the six trained sonographers. Each sonographer performed multiple data acquisitions in the right liver lobe using a lateral intercostal approach. A data acquisition was a single operator button press that recorded a B-mode image, radio-frequency data, and the SWS value. AC and BSC were calculated from the radio-frequency data using the reference phantom method. SWS was calculated automatically using product software. Intraclass correlation coefficient (ICC) and within-subject coefficient of variation (wCV) were calculated for applicable metrics.ResultsSixty-one participants were recruited. Inter-sonographer ICC was 0.86 (95% confidence interval: 0.77-0.92) for AC and 0.87 (0.78-0.92) for log-transformed BSC (logBSC = 10log10BSC) using one acquisition per sonographer. ICC was 0.88 (0.80-0.93) for both AC and logBSC averaging 5 acquisitions. ICC for SWS was 0.57 (0.29-0.74) using one acquisition per sonographer, and 0.84 (0.66-0.93) using 10 acquisitions. The wCV was ~7% for AC, and 19-43% for SWS, depending on number of acquisitions.ConclusionsHepatic AC, BSC and SWS measures on a clinical scanner have good inter-sonographer reproducibility in adults with known or suspected NAFLD. Multiple acquisitions are required for SWS but not AC or BSC to achieve good inter-sonographer reproducibility.Key points• AC, BSC and SWS measurements are reproducible in adults with NAFLD. • Inter-sonographer reproducibility of SWS measurement improves with more acquisitions being averaged. • Multiple acquisitions are required for SWS but not AC or BSC

Optimization of region-of-interest sampling strategies for hepatic MRI proton density fat fraction quantification.

BackgroundClinical trials utilizing proton density fat fraction (PDFF) as an imaging biomarker for hepatic steatosis have used a laborious region-of-interest (ROI) sampling strategy of placing an ROI in each hepatic segment.PurposeTo identify a strategy with the fewest ROIs that consistently achieves close agreement with the nine-ROI strategy.Study typeRetrospective secondary analysis of prospectively acquired clinical research data.PopulationA total of 391 adults (173 men, 218 women) with known or suspected NAFLD.Field strength/sequenceConfounder-corrected chemical-shift-encoded 3T MRI using a 2D multiecho gradient-recalled echo technique.AssessmentAn ROI was placed in each hepatic segment. Mean nine-ROI PDFF and segmental PDFF standard deviation were computed. Segmental and lobar PDFF were compared. PDFF was estimated using every combinatorial subset of ROIs and compared to the nine-ROI average.Statistical testingMean nine-ROI PDFF and segmental PDFF standard deviation were summarized descriptively. Segmental PDFF was compared using a one-way analysis of variance, and lobar PDFF was compared using a paired t-test and a Bland-Altman analysis. The PDFF estimated by every subset of ROIs was informally compared to the nine-ROI average using median intraclass correlation coefficients (ICCs) and Bland-Altman analyses.ResultsThe study population's mean whole-liver PDFF was 10.1 ± 8.9% (range: 1.1-44.1%). Although there was no significant difference in average segmental (P = 0.452) or lobar (P = 0.154) PDFF, left and right lobe PDFF differed by at least 1.5 percentage points in 25.1% (98/391) of patients. Any strategy with ≥4 ROIs had ICC &gt;0.995. 115 of 126 four-ROI strategies (91%) had limits of agreement (LOA) &lt;1.5%, including four-ROI strategies with two ROIs from each lobe, which all had LOA &lt;1.5%. 14/36 (39%) of two-ROI strategies and 74/84 (88%) of three-ROI strategies had ICC &gt;0.995, and 2/36 (6%) of two-ROI strategies and 46/84 (55%) of three-ROI strategies had LOA &lt;1.5%.Data conclusionFour-ROI sampling strategies with two ROIs in the left and right lobes achieve close agreement with nine-ROI PDFF.Level of evidence3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:988-994

Optimization of region-of-interest sampling strategies for hepatic MRI proton density fat fraction quantification.

BackgroundClinical trials utilizing proton density fat fraction (PDFF) as an imaging biomarker for hepatic steatosis have used a laborious region-of-interest (ROI) sampling strategy of placing an ROI in each hepatic segment.PurposeTo identify a strategy with the fewest ROIs that consistently achieves close agreement with the nine-ROI strategy.Study typeRetrospective secondary analysis of prospectively acquired clinical research data.PopulationA total of 391 adults (173 men, 218 women) with known or suspected NAFLD.Field strength/sequenceConfounder-corrected chemical-shift-encoded 3T MRI using a 2D multiecho gradient-recalled echo technique.AssessmentAn ROI was placed in each hepatic segment. Mean nine-ROI PDFF and segmental PDFF standard deviation were computed. Segmental and lobar PDFF were compared. PDFF was estimated using every combinatorial subset of ROIs and compared to the nine-ROI average.Statistical testingMean nine-ROI PDFF and segmental PDFF standard deviation were summarized descriptively. Segmental PDFF was compared using a one-way analysis of variance, and lobar PDFF was compared using a paired t-test and a Bland-Altman analysis. The PDFF estimated by every subset of ROIs was informally compared to the nine-ROI average using median intraclass correlation coefficients (ICCs) and Bland-Altman analyses.ResultsThe study population's mean whole-liver PDFF was 10.1 ± 8.9% (range: 1.1-44.1%). Although there was no significant difference in average segmental (P = 0.452) or lobar (P = 0.154) PDFF, left and right lobe PDFF differed by at least 1.5 percentage points in 25.1% (98/391) of patients. Any strategy with ≥4 ROIs had ICC &gt;0.995. 115 of 126 four-ROI strategies (91%) had limits of agreement (LOA) &lt;1.5%, including four-ROI strategies with two ROIs from each lobe, which all had LOA &lt;1.5%. 14/36 (39%) of two-ROI strategies and 74/84 (88%) of three-ROI strategies had ICC &gt;0.995, and 2/36 (6%) of two-ROI strategies and 46/84 (55%) of three-ROI strategies had LOA &lt;1.5%.Data conclusionFour-ROI sampling strategies with two ROIs in the left and right lobes achieve close agreement with nine-ROI PDFF.Level of evidence3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:988-994

Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity.

OBJECTIVES:To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity. STUDY DESIGN:We evaluated children aged 9-17 years with obesity for the presence of NAFLD. Diseases other than NAFLD were excluded by history and laboratories. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction. The diagnostic accuracy of ALT for detecting NAFLD was evaluated. RESULTS:The study included 408 children with obesity that had a mean age of 13.2 years and mean body mass index percentile of 98.0. The study population had a mean ALT of 32 U/L and median hepatic magnetic resonance imaging proton density fat fraction of 3.7%. The estimated prevalence of NAFLD was 26.0% (95% CI 24.2%-27.7%), 29.4% in male patients (CI 26.1%-32.7%) and 22.6% in female patients (CI 16.0%-29.1%). Optimal ALT cut-point was 42 U/L (47.8% sensitivity, 93.2% specificity) for male and 30 U/L (52.1% sensitivity, 88.8% specificity) for female patients. The classification and regression tree model with sex, ALT, and insulin had 80% diagnostic accuracy for NAFLD. CONCLUSIONS:NAFLD is common in children with obesity, but NAFLD and obesity are not concomitant. In children with obesity, NAFLD is present in nearly one-third of boys and one-fourth of girls