The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

Overestimation of fibrinogen concentration in cryoprecipitate by repeated freeze-thawing with long thawing period as used in the Clauss method.

BACKGROUND: Cryoprecipitate (CRY) is widely used for treating acquired hypofibrinogenemia. During our study to determine an optimal preparation method, we noticed that the measurement of fibrinogen concentration in CRY had a risk of overestimation. We analyzed this condition and mechanism. STUDY DESIGN AND METHODS: CRY was prepared from fresh frozen plasma (FFP) under four conditions: A, 30 h thawing time, 2 cycles; B, 24 h thawing time, 2 cycles; C, 30 h thawing time, 1 cycle; and D, 24 h thawing time, 1 cycle. Then, fibrinogen concentrations in CRY and cryosupernatant (CS) were measured by the Clauss method. RESULTS: Purification (CRY/CRY+CS) and recovery (CRY/FFP) rates in CRY prepared under 2-cycle conditions were higher than those under 1 cycle. However, recovery rates often exceeded 100%, particularly in the case of CRY prepared under A condition, and fibrinogen concentrations calculated by direct measurement were higher than those indirectly calculated from FFP and CS, suggesting an overestimation of fibrinogen values. The level of soluble fibrin monomer complex was considerably higher in CRY prepared under A than under D condition, indicating that CRY adopted a hypercoagulated state. We further found that repeated thawing/freezing increased fibrinogen values as measured by the Clauss method while mechanical vortexing did not. DISCUSSION: Our findings suggest that direct assessment of fibrinogen contents in CRY prepared by repeated freeze-thawing with a longer thawing period presents a higher risk of overestimation. For the purpose of quality control, we propose an alternative method to indirectly estimate fibrinogen concentrations in CRY from those of CS and FFP.

Deep Learning Reconstruction of Diffusion-weighted MRI Improves Image Quality for Prostatic Imaging.

Background Deep learning reconstruction (DLR) may improve image quality. However, its impact on diffusion-weighted imaging (DWI) of the prostate has yet to be assessed. Purpose To determine whether DLR can improve image quality of diffusion-weighted MRI at b values ranging from 1000 sec/mm2 to 5000 sec/mm2 in patients with prostate cancer. Materials and Methods In this retrospective study, images of the prostate obtained at DWI with a b value of 0 sec/mm2, DWI with a b value of 1000 sec/mm2 (DWI1000), DWI with a b value of 3000 sec/mm2 (DWI3000), and DWI with a b value of 5000 sec/mm2 (DWI5000) from consecutive patients with biopsy-proven cancer from January to June 2020 were reconstructed with and without DLR. Image quality was assessed using signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) from region-of-interest analysis and qualitatively assessed using a five-point visual scoring system (1 [very poor] to 5 [excellent]) for each high-b-value DWI sequence with and without DLR. The SNR, CNR, and visual score for DWI with and without DLR were compared with the paired t test and the Wilcoxon signed rank test with Bonferroni correction, respectively. Apparent diffusion coefficients (ADCs) from DWI with and without DLR were also compared with the paired t test with Bonferroni correction. Results A total of 60 patients (mean age, 67 years; age range, 49-79 years) were analyzed. DWI with DLR showed significantly higher SNRs and CNRs than DWI without DLR (P < .001); for example, with DWI1000 the mean SNR was 38.7 ± 0.6 versus 17.8 ± 0.6, respectively (P < .001), and the mean CNR was 18.4 ± 5.6 versus 7.4 ± 5.6, respectively (P < .001). DWI with DLR also demonstrated higher qualitative image quality than DWI without DLR (mean score: 4.8 ± 0.4 vs 4.0 ± 0.7, respectively, with DWI1000 [P = .001], 3.8 ± 0.7 vs 3.0 ± 0.8 with DWI3000 [P = .002], and 3.1 ± 0.8 vs 2.0 ± 0.9 with DWI5000 [P < .001]). ADCs derived with and without DLR did not differ substantially (P > .99). Conclusion Deep learning reconstruction improves the image quality of diffusion-weighted MRI scans of prostate cancer with no impact on apparent diffusion coefficient quantitation with a 3.0-T MRI system. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Turkbey in this issue.

Small Cell Lung Cancer Staging: Prospective Comparison of Conventional Staging Tests, FDG PET/CT, Whole-Body MRI, and Coregistered FDG PET/MRI.

BACKGROUND. Whole-body MRI and FDG PET/MRI have shown encouraging results for staging of thoracic malignancy but are poorly studied for staging of small cell lung cancer (SCLC). OBJECTIVE. The purpose of our study was to compare the performance of conventional staging tests, FDG PET/CT, whole-body MRI, and FDG PET/MRI for staging of SCLC. METHODS. This prospective study included 98 patients (64 men, 34 women; median age, 74 years) with SCLC who underwent conventional staging tests (brain MRI; neck, chest, and abdominopelvic CT; and bone scintigraphy), FDG PET/CT, and whole-body MRI within 2 weeks before treatment; coregistered FDG PET/MRI was generated. Two nuclear medicine physicians independently reviewed conventional tests and FDG PET/CT examinations in separate sessions, and two chest radiologists independently reviewed whole-body MRI and FDG PET/MRI examinations in separate sessions. Readers assessed T, N, and M categories; TNM stage; and Veterans Administration Lung Cancer Study Group (VALSG) stage. Reader pairs subsequently reached consensus. Stages determined clinically during tumor board sessions served as the reference standard. RESULTS. Accuracy for T category was higher (p < .05) for whole-body MRI (94.9%) and FDG PET/MRI (94.9%) than for FDG PET/CT (85.7%). Accuracy for N category was higher (p < .05) for whole-body MRI (84.7%), FDG PET/MRI (83.7%), and FDG PET/CT (81.6%) than for conventional staging tests (75.5%). Accuracy for M category was higher (p < .05) for whole-body MRI (94.9%), FDG PET/MRI (94.9%), and FDG PET/CT (94.9%) than for conventional staging tests (84.7%). Accuracy for TNM stage was higher (p < .05) for whole-body MRI (88.8%) and FDG PET/MRI (86.7%) than for FDG PET/CT (77.6%) and conventional staging tests (72.4%). Accuracy for VALSG stage was higher (p < .05) for whole-body MRI (95.9%), FDG PET/MRI (95.9%), and FDG PET/CT (98.0%) than for conventional staging tests (82.7%). Interobserver agreement, expressed as kappa coefficients, ranged from 0.81 to 0.94 across imaging tests and staging endpoints. CONCLUSION. FDG PET/CT, whole-body MRI, and coregistered FDG PET/MRI outperformed conventional tests for various staging endpoints in patients with SCLC. Whole-body MRI and FDG PET/MRI outperformed FDG PET/CT for T category and thus TNM stage, indicating the utility of MRI for assessing extent of local invasion in SCLC. CLINICAL IMPACT. Incorporation of either MRI approach may improve initial staging evaluation in SCLC.

Selective Fabrication of Nanowires with High Aspect Ratios Using a Diffusion Mixing Reaction System for Applications in Temperature Sensing.

The selective fabrication of highly ordered nanowires with high aspect ratios was of low reproducibility, which remains a challenge for laboratory research. In this paper, we report a novel approach for selective fabrication of conductive nanowires on a solid surface via diffusion mixing reaction system formed by a chemical pen. The nanoscale-mixing region was achieved by appropriately adjusting the viscosity of the solution and other parameters with the aid of dyes functioned as a flow boundary indicator. Finite element simulations and analysis were performed to understand the generation of mixing regions and guide the improvement of the chemical pen design. Under the optimal parameters, high aspect ratio silver nanowires (aspect ratio ≈ 1800) were obtained. Silver nanowire arrays with uniform width, gradient width and complex patterns were successfully fabricated. The theoretical value of the temperature coefficient of resistance (TCR) for silver was 0.0038 Ω/°C. A single silver wire temperature sensor with 7-fold increase in temperature coefficient resistance (0.0261 Ω/°C) was fabricated to show the advantages of the chemical pen in the fabrication of nanosensors. With the freedom of the region, simple operability and applicability, the chemical pen was expected to a potential and advanced method for selective nanomodification and processing on subcellular interfaces.

Concerted Catalysis by Adjacent Palladium and Gold in Alloy Nanoparticles for the Versatile and Practical [2+2+2] Cycloaddition of Alkynes.

A Pd-Au alloy efficiently catalyzed the [2+2+2] cycloaddition of substituted alkynes. Whereas monometallic Pd and Au catalysts were totally ineffective, Pd-Au alloy nanoparticle catalysts with a low Pd/Au molar ratio showed high activity to give the corresponding polysubstituted arenes in high yields. A variety of substituted alkynes participated in various modes of cycloaddition under Pd-Au alloy catalysis. The Pd-Au alloy catalysts exhibited high air tolerance and reusability.

A novel method for rapid detection of Streptococcus pneumoniae antigens in blood.

In this study, we used "RAPIRUN(®)Streptococcus pneumoniae HS (otitis media/sinusitis) (RAPIRUN-HS)," a rapid S. pneumoniae antigen detection kit, to investigate methods for detecting S. pneumoniae antigens in blood of 32 bacterial pneumonia patients. We simultaneously performed PCR to detect S. pneumoniae in blood samples. The results of these tests were compared based on pneumonia severity, determined using the Pneumonia Severity Index (PSI) score classification. Four S. pneumoniae PCR-positive patients of the six severe pneumococcal pneumonia patients (PSI risk class IV/V) also tested positive using RAPIRUN-HS. Twenty-four mild to moderate pneumonia patients (PSI risk class I-III) were S. pneumoniae PCR-negative; of these, 21 tested negative using RAPIRUN-HS. The pneumococcal pneumonia patients testing positive using RAPIRUN-HS had low leukocyte counts and elevated C-reactive protein and procalcitonin levels, indicating that RAPIRUN-HS results were correlated with pneumonia severity. The time course evaluations of the laboratory tests for severe pneumococcal pneumonia patients showed that RAPIRUN-HS and S. pneumoniae PCR yielded positive results earlier than the changes in procalcitonin and IL-6. Thus, concomitant pneumococcal bacteremia was strongly suspected in patients testing positive using RAPIRUN-HS. In conclusion, RAPIRUN-HS may be useful for determining whether to admit patients into hospitals and selecting the appropriate antimicrobial agents.

Impact of iodine contrast media on gamma camera-based GFR and factors affecting the difference between serum creatinine-based estimated GFR and Gate's GFR.

OBJECTIVE: We aimed to elucidate the factors underlying the difference between estimated glomerular filtration rate (eGFR) calculated from serum creatinine and Gate's GFR (gGFR) measured using technetium-99m diethylene triamine pentaacetic acid ( 99m Tc-DTPA) scintigraphy. METHODS: This study was based on consecutive patients who underwent 99m Tc-DTPA scintigraphy at our hospital between January 2021 and December 2022 and whose blood serum creatinine data were obtained on the same day as the 99m Tc-DTPA scintigraphy. Relationships between the ratio of gGFR and eGFR (gGFR/eGFR) and age, sex, BMI, visceral fat, psoas muscle index (PMI), serum blood urea nitrogen, and creatinine level were investigated based on 75 patients. Additionally, for 44 patients who had two or more follow-up DTPA studies, we compared gGFR values for studies that used iodine contrast media (ICM) for computed tomography before same-day 99m Tc-DTPA studies and those that did not in the same patients. RESULTS: Weak correlations were observed between gGFR/eGFR and PMI ( r  = 0.30), BMI ( r  = 0.24), and the visceral fat area ( r  = 0.33). Multi-regression analyses showed that gGFR/eGFR was correlated with PMI ( ß â€…= 0.34, P  < 0.01) and approached significance with the visceral fat area ( ß â€…= 0.24, P  = 0.05). A significant difference was observed in gGFR between patients who received ICM before the 99m Tc-DTPA renogram and those who did not ( P  < 0.001, eGFR 80.5 ±â€…19.0 vs. 91.7 ±â€…27.8 ml/min). CONCLUSION: ICM administration temporarily decreased gGFR, and increased muscle mass increased the difference between eGFR and gGFR values.

Cloning and expression of the isocitrate lyase gene from a nitrogen-fixing bacterium, Azotobacter vinelandii, and functional analysis of the enzyme by site-directed mutagenesis.

The gene encoding isocitrate lyase (ICL) from a nitrogen-fixing mesophilic bacterium, Azotobacter vinelandii strain IAM1078, was cloned, and the gene expression was examined. When sodium acetate or glucose was used as carbon source, similar growth was observed in this bacterium, but the ICL activity of cells grown with the former source was 43-hold higher than those with the latter. In addition, northern blot analysis revealed that expression of the ICL gene was induced by acetate. Based on a comparison of the amino acid sequences of the ICLs of various organisms, the ICL of this bacterium was found to be classifiable into subfamily 3, one of two phylogenetic groups of eubacteial ICLs. Replacement of the Ile504 in the ICL by Met, which is conserved in the corresponding position of cold-adapted ICLs of psychrophlic bacteria, resulted in decreased thermostability of activity, indicating that this amino acid residue is involved in thermal properties of this enzyme.

Allee effect in the selection for prime-numbered cycles in periodical cicadas.

Periodical cicadas are well known for their prime-numbered life cycles (17 and 13 years) and their mass periodical emergences. The origination and persistence of prime-numbered cycles are explained by the hybridization hypothesis on the basis of their lower likelihood of hybridization with other cycles. Recently, we showed by using an integer-based numerical model that prime-numbered cycles are indeed selected for among 10- to 20-year cycles. Here, we develop a real-number-based model to investigate the factors affecting the selection of prime-numbered cycles. We include an Allee effect in our model, such that a critical population size is set as an extinction threshold. We compare the real-number models with and without the Allee effect. The results show that in the presence of an Allee effect, prime-numbered life cycles are most likely to persist and to be selected under a wide range of extinction thresholds.

State-of-the-art MR Imaging for Thoracic Diseases.

Since thoracic MR imaging was first used in a clinical setting, it has been suggested that MR imaging has limited clinical utility for thoracic diseases, especially lung diseases, in comparison with x-ray CT and positron emission tomography (PET)/CT. However, in many countries and states and for specific indications, MR imaging has recently become practicable. In addition, recently developed pulmonary MR imaging with ultra-short TE (UTE) and zero TE (ZTE) has enhanced the utility of MR imaging for thoracic diseases in routine clinical practice. Furthermore, MR imaging has been introduced as being capable of assessing pulmonary function. It should be borne in mind, however, that these applications have so far been academically and clinically used only for healthy volunteers, but not for patients with various pulmonary diseases in Japan or other countries. In 2020, the Fleischner Society published a new report, which provides consensus expert opinions regarding appropriate clinical indications of pulmonary MR imaging for not only oncologic but also pulmonary diseases. This review article presents a brief history of MR imaging for thoracic diseases regarding its technical aspects and major clinical indications in Japan 1) in terms of what is currently available, 2) promising but requiring further validation or evaluation, and 3) developments warranting research investigations in preclinical or patient studies. State-of-the-art MR imaging can non-invasively visualize lung structural and functional abnormalities without ionizing radiation and thus provide an alternative to CT. MR imaging is considered as a tool for providing unique information. Moreover, prospective, randomized, and multi-center trials should be conducted to directly compare MR imaging with conventional methods to determine whether the former has equal or superior clinical relevance. The results of these trials together with continued improvements are expected to update or modify recommendations for the use of MRI in near future.

Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study.

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.

Historical effect in the territoriality of ayu fish.

Ayu fish form algae-feeding territories in a river during a non-breeding (growing) season. We build a cost-benefit theory to describe the breakdown and formation of territory. In the early stage of a growing season, all fish hold territories at low densities. Once all territory sites are occupied, excess fish become floaters. When fish density further increases, a phase transition occurs: all the territories suddenly break down and fish form a school. In contrast, when the fish density is decreased, territories are suddenly formed from the school. Both theory and experiments demonstrate that ayu should exhibit a historical effect: the breakdown and formation processes of territory are largely different. In particular, the theory in formation process predicts a specific fish behavior: an "attempted territory holder" that tries to have a small territory emerges just before the formation of territory.

Synthesis and electronic properties of π-expanded carbazole-based porphyrins.

Peripheral π-expansion of carbazole-based porphyrins was achieved for the first time by the Pt-catalyzed cyclization and the incorporation of a benzocarbazole unit. These two types of fused porphyrins showed red-shifted and broad NIR absorption due to the expanded π-conjugation as confirmed by NIR absorption spectroscopy and DFT calculations.

Elaborately programmed nanowires fabricated using a tapered push-pull nozzle system.

Elaborately programmed silver nanowire arrays can be prepared using a tapered push-pull nozzle system (TPPNS), which is used to directly write micro-nano wires on a substrate via a two-reagent reaction in the diffusion mixing region. The wires could be precisely positioned on the substrate and their width could be freely controlled from the micro to the nano scale, indicating an advance in the methodologies of controlling and fabricating nanowires. The as-prepared silver three-electrode device can serve as a three-electrode sensor.

Attempt to Harvest a Sufficient Number of Mononuclear Cells in an Appropriate Blood Product Volume By Modification of the Default Apheresis Setting.

To harvest for T cell therapy, a 1.6-fold higher number of CD3+ T cells was collected with MNC mode (N = 10) compared with Auto PBSC mode (N = 5) in COBE Spectra cell separator, but the blood product volume was increased by 3.5-fold. For therapeutic angiogenesis therapy, apheresis was initially performed using Auto PBSC mode (N = 4) to fine tune the blood product volume to omit cell concentration, but the collected number of mononuclear cells was lower than expected. However, an increase of the harvest cycle number from 3.8 ± 0.5 to 7.4 ± 2.0 cycles (N = 19) resulted in a 2.1-fold higher number of collected mononuclear cells (8.7 ± 4.1 × 109 vs. 4.1 ± 1.0 × 109 cells, P < 0.05). The increase in blood product volume by this modification appeared to be lower than that expected with MNC mode. These data show that optimal harvesting can be achieved by modification of default collection settings.

Development of mixed-type autoimmune hemolytic anemia and Evans' syndrome following chicken pox infection in a case of low-titer cold agglutinin disease.

We describe a patient with low-titer cold agglutinin disease (CAD) who developed mixed-type autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenia following chicken pox infection. At least 1 year before admission to hospital, the patient had mild hemolytic anemia associated with low-titer cold agglutinins. A severe hemolytic crisis and thrombocytopenia (Evans' syndrome) occurred several days after infection with chicken pox, and the patient was referred to our hospital. Serological findings revealed the presence of both cold agglutinins and warm-reactive autoantibodies against erythrocytes, and the diagnosis was mixed-type AIHA. Following steroid therapy, the hemoglobin (Hb) level and platelet count improved. The patient was closely followed over a 10-year period with recurrent documented hemolysis after viral or bacterial infections. Warm-reactive autoantibodies have not been detected in the last 2 years, and only the immunoglobulin M anti-I cold agglutinins with a low titer and wide thermal amplitude have remained unchanged. Therefore, the patient has received at least 10 mg prednisolone daily to maintain a Hb level of 10 g/dL. To the best of our knowledge, no adult case of low-titer CAD that has evolved into mixed-type AIHA and Evans' syndrome after chicken pox infection has been previously reported in the literature.

Fast Fourier transform analysis of pulmonary nodules on computed tomography images from patients with lung cancer.

PURPOSE: The outlines of primary lung cancers are more complicated than those of metastatic lung tumors on computed tomography (CT) images. This feature is useful for clarifying the diagnosis of pulmonary nodules before surgery. We applied fast Fourier transform (FFT) analysis for quantification of complexity of tumor outline. METHODS: Sequential cases of 72 primary lung cancers (Group PL) and 54 metastatic lung tumors (Group MT) were included. The outline of each tumor on chest CT images was described using polar coordinates, and converted to rectangular coordinates, yielding wave data of the tumor outline. The FFT was then used to analyze the wave data. The complexity index (Cxi) was defined as the sum of the amplitude of all harmonics over a fundamental frequency. RESULTS: The Cxi was higher (P <0.0001) for group PL (10.3 ± 6.7 mm) than for group MT (3.2 ± 2.4 mm), and it was correlated with tumor diameter in both groups. The cut-off equation "Cxi = 0.127 DT + 2.23" provided the highest diagnostic accuracy for distinguishing Group PL from Group MT such as a sensitivity of 95.8%, a specificity of 81.5%, and an accuracy of 89.7%. CONCLUSION: FFT analysis appears useful for quantification of complexity of the tumor outline.