The image quality of deep-learning image reconstruction of chest CT images on a mediastinal window setting.

AIM: To assess the image quality of deep-learning image reconstruction (DLIR) of chest computed tomography (CT) images on a mediastinal window setting in comparison to an adaptive statistical iterative reconstruction (ASiR-V). MATERIALS AND METHODS: Thirty-six patients were evaluated retrospectively. All patients underwent contrast-enhanced chest CT and thin-section images were reconstructed using filtered back projection (FBP); ASiR-V (60% and 100% blending setting); and DLIR (low, medium, and high settings). Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were evaluated objectively. Two independent radiologists evaluated ASiR-V 60% and DLIR subjectively, in comparison with FBP, on a five-point scale in terms of noise, streak artefact, lymph nodes, small vessels, and overall image quality on a mediastinal window setting (width 400 HU, level 60 HU). In addition, image texture of ASiR-Vs (60% and 100%) and DLIR-high was analysed subjectively. RESULTS: Compared with ASiR-V 60%, DLIR-med and DLIR-high showed significantly less noise, higher SNR, and higher CNR (p<0.0001). DLIR-high and ASiR-V 100% were not significantly different regarding noise (p=0.2918) and CNR (p=0.0642). At a higher DLIR setting, noise was lower and SNR and CNR were higher (p<0.0001). DLIR-high showed the best subjective scores for noise, streak artefact, and overall image quality (p<0.0001). Compared with ASiR-V 60%, DLIR-med and DLIR-high scored worse in the assessment of small vessels (p<0.0001). The image texture of DLIR-high was significantly finer than that of ASIR-Vs (p<0.0001). CONCLUSIONS: DLIR-high improved the objective parameters and subjective image quality by reducing noise and streak artefacts and providing finer image texture.

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.

BACKGROUND: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. PATIENTS AND METHODS: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH. RESULTS: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. CONCLUSIONS: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

Hepatitis B virus reactivation in patients with rheumatoid arthritis: Analysis of the National Database of Japan.

This study aimed to determine the incidence and risk factors for hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) undergoing immunosuppressive therapy. The National Database of Japan, in which insurance claim data have been comprehensively accumulated, was utilized. The subjects were 76 641 RA patients who were plausibly initiated on immunosuppressive therapy from April 2013 to March 2014. Laboratory tests of the hepatitis B surface antigen, anti-hepatitis B virus surface antibody, and anti-hepatitis B virus core antibody were performed in 28.23%, 12.52% and 14.63% of patients, respectively, when the therapy was initiated. We found that HBV reactivation and fulminant hepatitis occurred in both the patients with and without HBV DNA monitoring, indicating insufficient monitoring in Japan during the study. The cumulative incidence of HBV reactivation over 24 months was 1.57% (95% confidence interval [CI] = 1.28%-1.92%) in the monitoring group, which consisted of those with resolved HBV infection. Glucocorticoid administration was a potent risk factor for HBV reactivation (hazard ratio [HR]  = 1.70, 95% CI = 1.26-2.29, P = .001 in all subjects, and HR = 1.82, 95% CI = 1.18-2.81, P = .007 in the nonmonitoring group), although it was not statistically significant in the monitoring group (HR = 1.49, 95% CI = 0.99-2.26 and P = .057). No significant risk difference was observed between single administration of methotrexate and biological drugs.

Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers.

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.

Efficacy and safety of live varicella zoster vaccine in diabetes: a randomized, double-blind, placebo-controlled trial.

AIMS: To elucidate varicella zoster virus (VZV)-specific cell-mediated immunity and humoral immunogenicity against live attenuated Oka varicella zoster vaccine concurrently vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in elderly people with diabetes mellitus. METHODS: This double-blind randomized controlled single-centre study of 60-70-year-old people with diabetes compared immunity and safety profiles 3 months after one dose of varicella zoster vaccine or placebo. PPSV23 was immunized simultaneously. Primary analysis evaluated cell-mediated immunity using the VZV skin test. Secondary analyses were a VZV interferon-γ enzyme-linked immunospot (ELISPOT) assay and immunoadherence haemagglutination test. Adverse experiences were recorded using diary questionnaires. RESULTS: By intent-to-treat analysis, 27 participants with diabetes who had been administered the vaccine were compared with 27 participants who were given a placebo. Changes in skin test scores were 0.41 ± 0.80 and 0.11 ± 0.93 (P = 0.2155), and geometric mean fold rises of the ELISPOT counts were 1.2 [95% confidence interval (CI) 0.2, 7.9] and 1.2 (95% CI 0.2, 7.3) (P = 0.989) in the vaccine and placebo groups, respectively. The geometric mean titre did not increase 3 months after vaccination in either group. No vaccination-related severe adverse experience was reported and no participant developed herpes zoster. DISCUSSION: Our previous results demonstrated that varicella zoster vaccine safely enhanced VZV-specific immunity in elderly people with or without diabetes. The results of this study showed that varicella zoster vaccine can be used safely, but it cannot boost virus-specific immunity in elderly people with diabetes when administered with concurrent PPSV23. Alternative strategies are needed to prevent VZV-associated diseases in this population.

A peptide microarray fabricated on a non-fouling phosphatidylcholine-polymer-coated surface for a high-fidelity analysis of a cellular kinome.

Phosphatidylcholine-polymer-coated plastic slides were utilized for the fabrication of peptide microarrays for cellular kinome analysis. According to the non-fouling features of the surface, the signal-to-noise ratio of the detection of phosphorylated peptides improved by about 100-fold from that of a peptide microarray fabricated on a glass slide blocked by a commercial BSA-based reagent. When the phosphatidylcholine-polymer-coated peptide microarray was applied to the analysis of the kinome of HCC827 cells, hyperactivation of c-Src and EGFR were successfully detected.

Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study.

AIMS: Early studies have shown that magnesium intake decreases the risk of Type 2 diabetes, but the results are still inconsistent. We prospectively examined the association between magnesium intake and incidence of Type 2 diabetes in a general Japanese population. METHODS: A total of 1999 subjects without diabetes aged 40-79 years who underwent a 75-g oral glucose tolerance test were followed up prospectively for a mean of 15.6 years. RESULTS: During the follow-up, 417 subjects developed Type 2 diabetes. The age- and sex-adjusted incidence of Type 2 diabetes significantly decreased with increasing magnesium intake quartile levels (≤ 148.5, 148.6-171.5, 171.6-195.5 and ≥ 195.6 mg/day, P for trend = 0.01). In multivariate analyses, after adjusting for comprehensive risk factors and other dietary factors, the hazard ratio of Type 2 diabetes was 0.67 (95% CI 0.49-0.92; P = 0.01) in the third quartile and 0.63 (95% CI 0.44-0.90; P = 0.01) in the highest quartile compared with the first quartile. In addition, the risk of Type 2 diabetes was 14% lower (P = 0.04) for a 1-sd increment of log-transformed magnesium intake in the multivariate-adjusted model. In stratified analysis, there were statistically significant interactions between magnesium intake and levels of homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein or alcohol intake on the risk of Type 2 diabetes (all P < 0.05). CONCLUSIONS: Our findings suggest that increased magnesium intake was a significant protective factor for the incidence of Type 2 diabetes in the general Japanese population, especially among subjects with insulin resistance, low-grade inflammation and a drinking habit.

Functional variants in the thromboxane A2 receptor gene are associated with lung function in childhood-onset asthma.

BACKGROUND: The thromboxane A2 receptor (TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes. OBJECTIVE: To investigate the association of TBXA2R polymorphisms with asthma susceptibility and related phenotypes and to identify functionally relevant polymorphisms. METHODS: We performed comprehensive sequencing of the TBXA2R gene in 48 Japanese control subjects and found a set of variants (SNP1 G>T rs2238634, SNP2 T>G rs2238633, SNP3 C>T rs2238632 and SNP4 G>A rs2238631) in intron 1 in linkage disequilibrium with c.795 T>C rs1131882, which was previously reported to be associated with asthma and related phenotypes. To investigate the effect of four common haplotypes (H1, H2, H3 and H4) on transcriptional activity, we performed a luciferase assay in primary bronchial smooth muscle cells (BSMCs) and human airway epithelial cells (BEAS-2B). We also studied the haplotype association with lung function, TBXA2R mRNA levels, and eosinophil fraction/count in peripheral blood in childhood-onset asthma patients and/or controls. RESULTS: H2 and H4, containing minor alleles of SNP2 and SNP3, had significantly higher transcriptional activities than H1 consisting of major alleles (P < 0.001 in BSMCs and BEAS-2B). Homozygotes for redefined haplotype h2 corresponding to minor alleles of SNP2 and SNP3 were associated with lower lung function in childhood-onset asthma patients compared to other zygotes (baseline Forced expiratory volume in one second (FEV1)/ Forced vital capacity (FVC) and Forced expiratory flow between 25% and 75% of the FVC (%FEF(25-75%)): P = 0.00201 and 0.0128, respectively, and post-bronchodilator FEV1/FVC and %FEF(25-75%): P = 0.00224 and 0.0393 respectively). Haplotype h2 was also associated with higher mRNA levels in control peripheral blood cells and higher blood eosinophil fractions and counts in female controls. CONCLUSIONS AND CLINICAL RELEVANCE: Genetic variants were identified in the TBXA2R gene that influenced transcriptional activity and were associated with asthma-related phenotypes. Thromboxane pathways may therefore play important roles in airway inflammation and remodelling in asthma patients.

Occurrence and reduction of human viruses, F-specific RNA coliphage genogroups and microbial indicators at a full-scale wastewater treatment plant in Japan.

AIMS: To evaluate and compare the reductions of human viruses and F-specific coliphages in a full-scale wastewater treatment plant based on the quantitative PCR (qPCR) and plate count assays. METHODS AND RESULTS: A total of 24 water samples were collected from four locations at the plant, and the relative abundance of human viruses and F-RNA phage genogroups were determined by qPCR. Of the 10 types of viruses tested, enteric adenoviruses were the most prevalent in both influent and effluent wastewater samples. Of the different treatment steps, the activated sludge process was most effective in reducing the microbial loads. Viruses and F-RNA phages showed variable reduction; among them, GI and GIII F-RNA phages showed the lowest and the highest reduction, respectively. CONCLUSIONS: Ten types of viruses were present in wastewater that is discharged into public water bodies after treatment. The variability in reduction for the different virus types demonstrates that selection of adequate viral indicators is important for evaluating the efficacy of wastewater treatment and ensuring the water safety. SIGNIFICANCE AND IMPACT OF THE STUDY: Our comprehensive analyses of the occurrence and reduction of viruses and indicators can contribute to the future establishment of appropriate viral indicators to evaluate the efficacy of wastewater treatment.

ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Risk of Herpes zoster in patients with underlying diseases: a retrospective hospital-based cohort study.

PURPOSE: To determine the incidence of Herpes zoster in patients with one of 17 specific underlying diseases compared with that in patients with other underlying diseases. METHODS: We conducted a retrospective hospital-based cohort study using data from patients' electronic medical records for the period 2001-2007 of the Kitano Hospital Research Database. These analyses included 55,492 patients with one of 17 underlying diseases, which were those reported as related to the contraction of Herpes zoster. Of these, 769 patients contracted Herpes zoster. The main outcome measure was the clinical diagnosis of Herpes zoster. RESULTS: The adjusted hazard ratios (95% confidence interval) for Herpes zoster in patients with the 17 diseases were compared with other patients, with the following results: brain tumor [3.84 (2.51-5.88)], lung cancer [2.28 (1.61-3.22)], breast cancer [2.41 (1.52-3.82)], esophageal cancer [4.19 (2.16-8.11)], gastric cancer [1.95 (1.39-2.72)], colorectal cancer [1.85 (1.33-2.56)], gynecologic cancer [3.45 (2.08-5.70)], malignant lymphoma [8.23 (6.53-10.38)], systemic lupus erythematosus [3.90 (2.66-5.70)], rheumatoid arthritis [2.00 (1.60-2.50)], diabetes mellitus [2.44 (2.10-2.85)], hypertension [2.04 (1.75-2.38)], renal failure [2.14 (1.65-2.79)], and disk hernia [2.18 (1.52-3.13)]. CONCLUSIONS: Patients with diabetes mellitus, renal failure, and malignancies have a 1.8-8.4-fold higher risk of a Herpes zoster event than patients with other diseases. Future studies should investigate alteration of the immune system in the underlying diseases and approaches for Herpes zoster prevention.

Cranio-lenticulo-sutural dysplasia associated with defects in collagen secretion.

Cranio-lenticulo-sutural dysplasia (CLSD) is a rare autosomal recessive syndrome manifesting with large and late-closing fontanels and calvarial hypomineralization, Y-shaped cataracts, skeletal defects, and hypertelorism and other facial dysmorphisms. The CLSD locus was mapped to chromosome 14q13-q21 and a homozygous SEC23A F382L missense mutation was identified in the original family. Skin fibroblasts from these patients exhibit features of a secretion defect with marked distension of the endoplasmic reticulum (ER), consistent with SEC23A function in protein export from the ER. We report an unrelated family where a male proband presented with clinical features of CLSD. A heterozygous missense M702V mutation in a highly conserved residue of SEC23A was inherited from the clinically unaffected father, but no maternal SEC23A mutation was identified. Cultured skin fibroblasts from this new patient showed a severe secretion defect of collagen and enlarged ER, confirming aberrant protein export from the ER. Milder collagen secretion defects and ER distention were present in paternal fibroblasts, indicating that an additional mutation(s) is present in the proband. Our data suggest that defective ER export is the cause of CLSD and genetic element(s) besides SEC23A may influence its presentation.

[Vacuum assisted closure for postoperative mediastinitis using a portable aspirator].

We report a case of successful treatment of a methicillin resistant Staphylococcus aureus (MRSA) mediastinitis by vacuum assisted closure (VAC) using SB VAC system as a portable aspirator. A 67-year-old male with intellectual disability and diabetes mellitus suffered from angina pectoris and underwent on-pump coronary artery bypass grafting. He had a MRSA mediastinitis following the surgery. We started vancomycin administration and VAC. It was expected that using wall suction for VAC would be difficult because of his intellectual disability. So we performed VAC using SB VAC system as a portable aspirator. VAC therapy for mediastinitis after cardiac surgery is effective and SB VAC system can be used as a portable aspirator.

Positive association of genetic variants in the upstream region of NKX2-3 with Crohn's disease in Japanese patients.

BACKGROUND AND AIMS: A number of genome-wide association studies have been performed as a robust means of identifying susceptibility loci for Crohn's disease (CD). The loci detected after the completion of the HapMap project are quite concordant among these studies, suggesting that the results are reliable. Recently, the Wellcome Trust Case Control Consortium (WTCCC) reported the primary scanning of 17,000 individuals for seven diseases, including CD, and a subsequent study has validated these susceptible genetic variants in independent UK sample sets. The purpose of this study was to study the possible association of the variants reported by the WTCCC with CD in a Japanese population. PATIENTS AND METHODS: A total of 484 patients with CD and 470 healthy controls were examined. Seventeen genetic variants at eight newly identified loci, including IRGM, NKX2-3 and PTPN2, were genotyped using the TaqMan assay or the invader assay. RESULTS: A positive association signal presumably common to different ethnic groups for rs10883365 was detected in the upstream region of NKX2-3 (p = 0.019 under the genotypic model, p = 0.0065 under the allelic model, p = 0.019 under the recessive model, p = 0.036 under the dominant model). In addition to rs10883365, marginal associations for two single nucleotide polymorphisms (SNPs) were detected in the Japanese population; rs6887695 near IL12B and rs10761659 on 10q21. Further genotype-phenotype analysis found a significant association between rs6887695 and patients with pure ileal CD. CONCLUSIONS: The results indicate that the three loci are possible candidates for conferring susceptibility to CD in people of different ethnicities.

Effect of intestinal microbiota on the induction of regulatory CD25+ CD4+ T cells.

When oral tolerance was induced in either specific pathogen-free (SPF) or germ-free (GF) mice, ovalbumin (OVA) feeding before immunization induced oral tolerance successfully in SPF mice. On the other hand, OVA-specific immunoglobulin G1 (IgG1) and IgE titres in OVA-fed GF mice were comparable to those in phosphate-buffered saline-fed GF mice, thus demonstrating that oral tolerance could not be induced in GF mice. The frequencies of CD25(+) CD4(+)/CD4(+) cells in the mesenteric lymph node (MLN) and the absolute number of CD25(+) CD4(+) cells in the Peyer's patches and MLN of naive GF mice were significantly lower than those in naive SPF mice. In an in vitro assay, the CD25(+) CD4(+) cells from the naive SPF mice suppressed more effectively the proliferation of responder cells in a dose-dependent manner than those from the GF mice. In addition, the CD25(+) CD4(+) regulatory T (T(reg)) cells from the naive SPF mice produced higher amounts of interleukin (IL)-10 and transforming growth factor (TGF)-beta than those from the GF mice. When anti-TGF-beta neutralizing antibody, but not anti-IL-10 neutralizing antibody, was added to the in vitro proliferation assay, the suppressive effect of the CD25(+) CD4(+) T(reg) cells from the SPF mice was attenuated to the same level as that of the CD25(+) CD4(+) cells from the GF mice. In conclusion, the TGF-beta-producing CD25(+) CD4(+) T(reg) cells from the MLN of SPF mice played a major role in oral tolerance induction. In addition, as the regulatory function of the CD25(+) CD4(+) cells from the naive GF mice was much lower than that of the CD25(+) CD4(+) T(reg) cells from the SPF mice, indigenous microbiota are thus considered to contribute to the induction and maintenance of CD25(+) CD4(+) T(reg) cells.

Transient antiphospholipid antibodies associated with acute infections in children: a report of three cases and a review of the literature.

We describe two previously healthy children who had multiple ecchymoses several days after acute infection. In both cases, the prothrombin time (PT) and the activated partial thromboplastin time (APTT) were prolonged. Further examinations revealed the presence of lupus anticoagulant (LA), phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT), and low serum complement. In both cases, we confirmed the presence of a serum immune complex. The patients' symptoms improved spontaneously within 1 week, and all laboratory data normalized within several months. We also describe another asymptomatic case positive for LA and aPS/PT presumably associated with cytomegalovirus infection. The prevalence of transient antiphospholipid antibodies associated with viral infections in children must be much higher than we expected. We have to take it into consideration when we see abnormal coagulation results, but the occurrence of significant bleeding symptoms is rare.