Temporal subtraction CT with nonrigid image registration improves detection of bone metastases by radiologists: results of a large-scale observer study

To determine whether temporal subtraction (TS) CT obtained with non-rigid image registration improves detection of various bone metastases during serial clinical follow-up examinations by numerous radiologists. Six board-certified radiologists retrospectively scrutinized CT images for patients with history of malignancy sequentially. These radiologists selected 50 positive and 50 negative subjects with and without bone metastases, respectively. Furthermore, for each subject, they selected a pair of previous and current CT images satisfying predefined criteria by consensus. Previous images were non-rigidly transformed to match current images and subtracted from current images to automatically generate TS images. Subsequently, 18 radiologists independently interpreted the 100 CT image pairs to identify bone metastases, both without and with TS images, with each interpretation separated from the other by an interval of at least 30 days. Jackknife free-response receiver operating characteristics (JAFROC) analysis was conducted to assess observer performance. Compared with interpretation without TS images, interpretation with TS images was associated with a significantly higher mean figure of merit (0.710 vs. 0.658; JAFROC analysis, P = 0.0027). Mean sensitivity at lesion-based was significantly higher for interpretation with TS compared with that without TS (46.1% vs. 33.9%; P = 0.003). Mean false positive count per subject was also significantly higher for interpretation with TS than for that without TS (0.28 vs. 0.15; P < 0.001). At the subject-based, mean sensitivity was significantly higher for interpretation with TS images than that without TS images (73.2% vs. 65.4%; P = 0.003). There was no significant difference in mean specificity (0.93 vs. 0.95; P = 0.083). TS significantly improved overall performance in the detection of various bone metastases

Existence of serum HBe antigen and expression of liver HB surface and core antigens in hepatitis type B patients.

A study of 52 liver biopsies (47 hepatitis type B and 5 asymptomatic carriers) was performed to clarify the roles of HBe antigen (HBeAg), HB surface antigen (HBsAg) and HB core antigen (HBcAg). In this study, the Gudat classification was modified so as to classify the patterns of HB antigens into six reaction types including: type O (negative for both liver HBsAg and liver HBcAg), type III-A (characterized by a spotty HBsAg pattern) and type III-B (characterized from a sub-lobular to lobular HBsAg localization pattern). This classification enabled accurate prediction of the prognosis of hepatitis. Patients with positive serum HBeAg had either minimal hepatitis with mild clinical features or chronic aggressive hepatitis with severe clinical features. Ten patients negative for both HBeAg and HBeAb were all positive for liver HBcAg. In all 3 patients on corticosteroid administrations liver tissue was markedly positive for HBcAg and serum was usually positive for HBeAb.</p

Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons

Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (&amp;lt;65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency &amp;lt; 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study

Abstract Objective: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. Materials and methods: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. Results: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (−4.7 ± 2.0 kg, P < 0.001) and 2 weeks (−5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x – 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. Conclusions: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Stratigraphy and conodont and ammonoid ages of Upper Triassic Nakijin Formation in Hedomisaki area, Okinawa-jima, Japan

We present a lithostratigraphic, biostratigraphic (conodont and ammonoid), and petrographic study of Upper Triassic bedded limestones (Nakijin Formation) from Hedomisaki, northern Okinawa Island, Japan. The Hedomisaki limestones comprise two formations: Upper Triassic bedded limestone of the Nakijin Formation and massive limestone of the Hedomisaki Formation of unknown age. The Nakijin Formation is divided into three members: (1) lower = dark gray micritic limestone (ca. 110 m thick); (2) middle = clastic limestone (ca. 180 m thick); and (3) upper = clastic limestone with slump beds (ca. 110 m thick). Biostratigraphic datums based on conodont and ammonoid fossils show that the Nakijin Formation was deposited in the early Carnian through the middle Norian. Microfacies in the Nakijin Formation are classified into four major facies: (1) radiolarian limestone–mudstone; (2) thin-shelled bivalve mudstone–wackestone; (3) litho–bioclastic packstone; and (4) peloidal–bioclastic packstone. Facies 1 and 2 are dominated by planktonic biota, indicating a deep-water pelagic environment. The clastic limestones (3, 4) in the middle to upper member of the Nakijin Formation were likely deposited in a shallow-water environment on and around an oceanic seamount in an open ocean setting