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【Background】 Weight loss in patients with cancer is caused by cancer cachexia and chemotherapy-induced nausea and vomiting (CINV). Recent developments in antiemetic drugs have substantially improved CINV, but nutritional intervention did not improve body weight. This study aimed to investigate the effects of nutrition intervention with appropriate antiemetic treatment in patients with non-small-cell lung cancer during chemotherapy. 【Methods】 Patients received individualized nutrition counseling by a registered dietitian and were provided with oral supplements for 90 days. Body weight and other parameters were measured at baseline and after 90-day intervention. To evaluate this nutrition intervention, patients were also retrospectively set as control, and then body weight change was compared with inverse probability of treatment weights (IPTW) analysis. 【Results】 Ten patients received individualized nutrition counseling and were provided with oral supplements for 90 days. Of them, 7 patients consumed nutritional supplements, and the mean intake was 130 kcal/day. After 90-day intervention, the patients did not show significant weight and BMI loss during the course of cytotoxic chemotherapy. A total of 38 patients were retrospectively enrolled as controls. The number of the patients who gain the body weight after 90 days in the study cohort was significantly larger than that in the retrospective controls with the IPTW analysis (Odds Ratio (OR) = 8.4; 95% Confidence Interval (CI): 1.6-42; P = 0.01). 【Conclusion】 Early intensive nutrition intervention with appropriate antiemetic treatment prevents weight loss. Nutrition interventions might be also beneficial for quality of life, treatment response and survival.

BACKGROUND AND AIM Application of artificial intelligence in medicine is now attracting substantial attention. In the field of gastrointestinal endoscopy, computer-aided diagnosis (CAD) for colonoscopy is the most investigated area, although it is still in the preclinical phase. Because colonoscopy is carried out by humans, it is inherently an imperfect procedure. CAD assistance is expected to improve its quality regarding automated polyp detection and characterization (i.e. predicting the polyp's pathology). It could help prevent endoscopists from missing polyps as well as provide a precise optical diagnosis for those detected. Ultimately, these functions that CAD provides could produce a higher adenoma detection rate and reduce the cost of polypectomy for hyperplastic polyps. METHODS AND RESULTS Currently, research on automated polyp detection has been limited to experimental assessments using an algorithm based on ex vivo videos or static images. Performance for clinical use was reported to have >90% sensitivity with acceptable specificity. In contrast, research on automated polyp characterization seems to surpass that for polyp detection. Prospective studies of in vivo use of artificial intelligence technologies have been reported by several groups, some of which showed a >90% negative predictive value for differentiating diminutive (≤5 mm) rectosigmoid adenomas, which exceeded the threshold for optical biopsy. CONCLUSION We introduce the potential of using CAD for colonoscopy and describe the most recent conditions for regulatory approval for artificial intelligence-assisted medical devices.

Integration of solid-state nanopores and multichannel detection of signals from each nanopore are effective measures for realizing high-throughput nanopore sensors. In the present study, we demonstrated fabrication of Si3N4 membrane arrays and the simultaneous measurement of ionic currents through two nanopores formed in two adjacent membranes. Membranes with thicknesses as low as 6.4 nm and small nanopores with diameters of less than 2 nm could be fabricated using the poly-Si sacrificial-layer process and multilevel pulse-voltage injection. Using the fabricated nanopore membranes, we successfully achieved simultaneous detection of clear ionic-current blockades when single-stranded short homopolymers (poly(dA)60) passed through two nanopores. In addition, we investigated the signal crosstalk and leakage current among separated chambers. When two nanopores were isolated on the front surface of the membrane, there was no signal crosstalk or leakage current between the chambers. However, when two nanopores were isolated on the backside of the Si substrate, signal crosstalk and leakage current were observed owing to high-capacitance coupling between the chambers and electrolysis of water on the surface of the Si substrate. The signal crosstalk and leakage current could be suppressed by oxidizing the exposed Si surface in the membrane chip. Finally, the observed ionic-current blockade when poly(dA)60 passed through the nanopore in the oxidized chip was approximately half of that observed in the non-oxidized chip.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010.The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents.Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S.aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S.pneumoniae were 1.1% and 0.0%, respectively. Among H.influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K.pneumoniae and multi-drug resistant P.aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively.Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis., Journal of Infection and Chemotherapy, 21(6), pp.410-420; 2015

Objectives Zoledronate (ZOL) is usually used for prevention of skeletal-related events in cancer patients with bone metastases. The first administration of ZOL is occasionally associated with development of acute-phase reaction (APR), which is due to activation of γδ T cells. ZOL-related APR was associated with better overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in our previous retrospective study. However, it remains to be clarified whether γδ T cells are more activated in patients who experienced ZOL-related APR, and whether γδ T cell activation is involved in prolongation of OS. Materials and Methods Twenty-three patients with advanced NSCLC were recruited between 2012 and 2014 in this study. We administered ZOL to participants with standard care. The patient characteristics, change in γδ T cell counts and cytokines, OS, and skeletal-related event-free survival were compared between patients with APR (APR group) and those without APR (non-APR group). Results Ten patients (43.5%) experienced a ZOL-related APR. The number of γδ T cells at baseline in the APR group was significantly higher than that in the non-APR group. Serum interleukin-6 and tumor necrosis factor-α in the APR group were significantly increased, but no change in the number of γδ T cells was observed after the first administration of ZOL in both groups. OS in the APR group was significantly longer than that in the non-APR group (median survival time: 23.1 vs. 14.5 months, p Conclusion We showed that APR is related to higher numbers of γδ T cells at baseline and increased cytokines after the first ZOL administration, but not to proliferative responses of γδ T cells. In addition, better OS was observed in the APR group. Therefore, the number of γδ T cells might be a prognostic marker in patients with NSCLC.

Epidermal growth factor receptor (EGFR) gene mutation testing is essential for choosing appropriate treatment options in patients with advanced non-small cell lung cancer (NSCLC). However, a time delay occurs between histological diagnosis and molecular diagnosis in clinical situations. To minimize this delay, we developed a novel point-of-care test for EGFR mutations, based on a high-speed real-time polymerase chain reaction (PCR) system designated here as ultrarapid PCR combined with highly accurate bronchoscopic sampling. We investigated whether our system for detecting EGFR mutations was valid by comparing test results with those obtained using a commercialized EGFR mutation test. We obtained small amounts of bronchial lavage fluids after transbronchial biopsies (TBBs) were performed on enrolled patients (n=168) who underwent endobronchial ultrasonography using a guide sheath (EBUS-GS). EGFR mutation analysis was performed by ultrarapid PCR immediately after EBUS-GS-TBBs were obtained (on the same day). After pathological diagnoses of NSCLC, EGFR mutation status in formalin-fixed, paraffin- embedded samples was confirmed by the PCR-invader method, and the concordance rates between the PCR methods were compared. The total diagnostic yield of EBUS-GS-TBB was 91.0%. The positive concordance rates for detecting 19del and L858R with the ultrarapid PCR and PCR-invader methods were both 100%. Negative concordance rates were 97.2 and 98.1%, respectively. We also demonstrated a dramatic effect of early erlotinib administration, based on ultrarapid PCR results, for a 52-year-old woman suffering from respiratory failure due to severe intrapulmonary metastases with poor performance status. In conclusion, ultrarapid PCR combined with EBUS-GS-TBB enabled rapid and reliable point-of-care testing for EGFR mutations.

Chest computed tomography (CT) is not performed routinely or worldwide as the initial diagnostic procedure for patients with head and neck cancer (HNC). The significance of the chest CT scan for HNC diagnosis has not been thoroughly defined. The present study reports findings in an effort to broaden the acceptance and application of CT for HNC.Using medical records, we assessed initial chest CT scans of the patients with new-onset HNC between April 2004 and March 2010. The results were classified into three groups: nodules ≥ 1 cm, small nodules (1 cm) that were indeterminate and normal lungs without nodules. Lung nodules that increased in size and/or number at follow-up were regarded as malignant. First, the sensitivity of X-ray and CT for detection of lung nodules in patients with HNC was compared. Second, the nodules were estimated to be malignant or not malignant by follow-up chest CT. Third, statistical analyses were performed to determine the association between variables and distant lung metastases in patients with head and neck squamous cell carcinoma.In total, 332 patients underwent a chest CT scan as part of the initial examination. Lung nodules were detected on the initial chest CT in 77 patients: in contrast, lung nodules were detected on the initial chest X-ray in only five patients. On initial chest CT scans, lung nodules ≥ 1 cm were observed in 10 patients, small solitary lung nodules were observed in 67 patients, and lungs without nodules were observed in 255 patients. Lung nodules were detected in 77 (23.2%) patients, 25 (32.5%) of whom had malignant lung nodules. Moreover, in 18/67 patients (26.9%), small lung nodules initially classified as indeterminate were determined as malignant at follow-up. However, 30/255 patients (11.8%) without nodules at initial diagnosis developed lung nodules at follow-up. T3 or T4 disease (P = 0.006), N2 or N3 disease (P0.001) and stage 3 or 4 disease (P = 0.001) individually and significantly correlated with the development of lung metastases. In addition, lung nodules in initial CT scans (P = 0.004) and other distant metastases (P0.001) were significant predictors for the development of lung metastases at follow-up.Initial chest CT scan is recommended for patients with advanced HNC. Further, patients with advanced HNC with or without lung nodules, as detected on initial chest CT scans, should be followed up with additional scanning.

A forming process for heated sheet metal, such as hot-stamping, has limited use in deformable shapes. Higher temperature areas which have not yet come into contact with dies are more easily deformed; therefore, local deformation occurs at these areas which leads to breakage. To improve the formability of heated sheet metal, a deformation control technique utilizing the temperature dependence of flow stress is proposed. This technique can suppress local deformation by partial cooling around potential cracking areas to harden them before forming. In order to apply this technique to a variety of product shapes, a procedure to determine a suitable initial temperature distribution for deep drawing and biaxial stretching was developed with a coupled thermal structural simulation. In this procedure, finite elements exceeding forming limit strain are highlighted, and an initial temperature distribution is defined with areas of decreased temperature around the elements to increase their resistance to deformation. Subsequently, the partial cooling technique was applied to a deep drawing test with a heated steel sheet. The results of the experiment showed that the proposed technique improved 71% in the forming limit depth compared with results obtained using a uniform initial temperature distribution.

Previously we showed that Akt-suppressing agents, combined with amrubicin, synergistically inhibited the growth of small cell lung cancer cells. The combined effects of chemotherapeutic agents and Akt-suppressing agents, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, were evaluated in A549 lung adenocarcinoma cells harboring K-ras mutation and wild-type EGFR. Only amrubicin and not other chemotherapeutics (cisplatin, pemetrexed and paclitaxel) synergistically inhibited cell growth when combined with an Akt inhibitor, LY294002. The combination of amrubicin and LY294002 enhanced Annexin V binding to cells. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin. Two EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, suppressed Akt activity at clinically achievable concentrations and demonstrated synergism when combined with amrubicin. The suppression of K-ras expression by siRNA interfered with this synergism and inhibited both EGFR and Akt activity in A549 cells. In Ma10 cells, which harbor wild-type EGFR and K-ras, EGFR-TKIs neither suppressed Akt activity nor exhibited such synergism when combined with amrubicin. We concluded that the synergism by the combination of EGFR-TKI and amrubicin is attributable, at least partially, to K-ras mutation in A549 cells. The combination of EGFR-TKI and amrubicin may be a promising treatment for lung cancer with wild-type EGFR and K-ras mutation.

Background and Aim Endocytoscopy (EC) at ultra-high magnification enables in vivo visualization of cellular atypia of gastrointestinal mucosae. Clear images are essential for precise diagnosis by EC. The aim of the present study was to evaluate the optimal staining method for EC in the colon. Methods Thirty prospectively enrolled patients were allocated 1:1:1 to three distinct staining methods: 0.05% crystal violet (CV) alone, 1% methylene blue (MB) alone, or CV + MB (CM double). Normal rectal mucosae were stained with each dye and videos of EC images were recorded. Visibility of nuclei and gland formation after staining were evaluated as ‘recognizable’ or ‘not recognizable’. Time for each parameter to become ‘recognizable’ was measured, and the average times for the three staining regimens were compared. Results MB alone and CM double staining resulted in ‘recognizable’ (102 ± 27 vs 89 ± 22 s, P = 0.263) nuclei within comparable periods of time, whereas CV alone was unable to identify nuclei. Gland formation became ‘recognizable’ sooner after CM double staining than after MB alone (61 ± 16 vs 108 ± 24 s, P

Kenichi Takeda,1 Yuji Kawasaki,2 Kazumasa Yoshida,3 Yoji Nishida,3 Tomoya Harada,1 Kosuke Yamaguchi,2 Shizuka Ito,1 Kiyoshi Hashimoto,1 Shingo Matsumoto,1 Akira Yamasaki,1 Tadashi Igishi,1 Eiji Shimizu1 1Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Japan; 2Department of Regional Medicine, Faculty of Medicine, Tottori University, Yonago, Japan; 3Department of Rehabilitation Medicine, Yoka Hospital, Yabu, Japan Background: Upper-extremity exercise is for pulmonary rehabilitation. The 6-minute pegboard and ring test (6PBRT) was developed to evaluate arm exercise capacity in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to characterize the 6PBRT and evaluate its relationship with upper-extremity activities of daily living (ADLs) in COPD patients. Methods: Twenty outpatients with mild to very severe COPD underwent the 6PBRT and spirometry, and their maximal inspiratory and expiratory pressures and grip strength were measured. For the 6PBRT, subjects were asked to move as many rings as possible in 6 minutes, and the score was the number of moved rings during the 6-minute period. Upper-extremity ADLs were evaluated with the upper extremity activities subdomain of the modified Pulmonary Functional Status and Dyspnea Questionnaire. Upper-extremity ADLs were also measured objectively by using a wrist accelerometer every day for 1 week. Results: There was a positive correlation between 6PBRT score and inspiratory capacity (r = 0.71, P < 0.001), inspiratory capacity/total lung capacity predicted (r = 0.68, P < 0.01), and forced vial capacity (r = 0.57, P < 0.01). There was also a positive correlation between 6PBRT score and accelerometer count (r = 0.54, P < 0.05) and a negative correlation between 6PBRT score and arm activity score (ρ = -0.49, P < 0.05). Conclusion: The 6PBRT may be a predictive test to maintain and improve upper-extremity ADL during pulmonary rehabilitation in patients with COPD. Keywords: pulmonary rehabilitation, inspiratory capacity, COPD, wrist accelerometer, modified Pulmonary Functional Status and Dyspnea Questionnaire

SMARCA4-deficient thoracic sarcoma is a recently proposed new entity of soft tissue sarcomas with an undifferentiated round cell morphology that is diagnostically challenging. Here we report a case of this tumor where the diagnosis was established using limited samples and resources. A woman in her early 30s developed two intrathoracic masses. Biopsies for these lesions showed sheets of undifferentiated round/rhabdoid cells that retained SMARCB1 expression. Further analysis revealed a reduced SMARCA4 expression and a complete loss of SMARCA2 expression in tumor cells. Subsequent Sanger sequencing identified a nonsense c.1546A>T (p.516Lys>Ter) mutation in SMARCA4 and confirmed the diagnosis. Our case highlighted clinicopathological correlation and rational use of tissue sections for immunohistochemistry may enable to diagnose this tumor even when only limited samples are available. Recognition of this new entity is important for further understanding of the disease and the future development of specific therapies.

The practical use of solid-state nanopores for DNA sequencing requires easy fabrication of the nanopores, reduction of the DNA movement speed and reduction of the ionic current noise. Here, we report an integrated nanopore platform with a nanobead structure that decelerates DNA movement and an insulating polyimide layer that reduces noise. To enable rapid nanopore fabrication, we introduced a controlled dielectric breakdown (CDB) process into our system. DNA translocation experiments revealed that single nanopores were created by the CDB process without sacrificing performance in reducing DNA movement speed by up to 10 μs/base or reducing noise up to 600 pArms at 1 MHz. Our platform provides the essential components for proceeding to the next step in the process of DNA sequencing.

A 60-year-old man was diagnosed as multiple hepatic abscesses. Failure in the first empiric therapy led to extension into the pericardium, causing acute cardiac tamponade. Actinomyces species were not cultured from the pericardial effusion. The definitive diagnosis was acquired by ultrasound guided needle biopsy.

Objective : Health-care associated pneumonia (HCAP) is a new category of pneumonia. We investigated differences of epidemiology, pathogens, and outcomes be- tween HCAP patients in large hospitals and those in small hospitals. Methods : This was a retrospective observational study of patients hospitalized with HCAP from December 2009 to March 2010. HCAP was defined according to ATS/IDSA criteria. A large hospital was defined as 200 beds and a small hospital was 200 beds. Results : Of 117 patients, 61 patients were admitted to large hospitals and 56 patients were admitted to small hospitals. There was a significant difference of HCAP diagnostic criteria between the two groups. The A-DROP severity class was worse in the large hospital group than the small hospital group (P 0.05). Respiratory failure and disturbance of consciousness were more frequent in the large hospital group (P 0.05). The mortality rate was 8.2% n the large hospital group versus 1.8% in the small hospital group. Patients in the very severe A-DROP class had a high mortality rate of 33% in both groups. Conclusion : Patients with severe HCAP were more likely to be admitted to large hospitals. Patients in the very severe A-DROP class should receive intensive antibiotic therapy, but not all patients need broad-spectrum therapy. J. Med. Invest. 58 : 67-74, February, 2011

A 69-year-old woman with a history of cervical cancer was admitted to our hospital for further investigation of abnormal shadows on her chest roentgenogram. Histologic examination of transbronchial lung biopsy specimens revealed epithelioid cell granuloma, and Mycobacterium intracellulare was detected in the bronchial lavage fluid. The plasma level of (1→3)-beta-d-glucan was very high, and this elevated level was attributed to administration of sizofiran for treatment of cervical cancer 18 years previously. Therefore, in patients with cervical cancer, it is important to confirm whether or not sizofiran has been administered before measuring (1→3)-beta-d-glucan levels.

Background Computer-aided diagnosis (CAD) for colonoscopy may help endoscopists distinguish neoplastic polyps (adenomas) requiring resection from nonneoplastic polyps not requiring resection, potentially reducing cost. Objective To evaluate the performance of real-time CAD with endocytoscopes (×520 ultramagnifying colonoscopes providing microvascular and cellular visualization of colorectal polyps after application of the narrow-band imaging [NBI] and methylene blue staining modes, respectively). Design Single-group, open-label, prospective study. (UMIN [University hospital Medical Information Network] Clinical Trial Registry: UMIN000027360). Setting University hospital. Participants 791 consecutive patients undergoing colonoscopy and 23 endoscopists. Intervention Real-time use of CAD during colonoscopy. Measurements CAD-predicted pathology (neoplastic or nonneoplastic) of detected diminutive polyps (≤5 mm) on the basis of real-time outputs compared with pathologic diagnosis of the resected specimen (gold standard). The primary end point was whether CAD with the stained mode produced a negative predictive value (NPV) of 90% or greater for identifying diminutive rectosigmoid adenomas, the threshold required to "diagnose-and-leave" nonneoplastic polyps. Best- and worst-case scenarios assumed that polyps lacking either CAD diagnosis or pathology were true- or false-positive or true- or false-negative, respectively. Results Overall, 466 diminutive (including 250 rectosigmoid) polyps from 325 patients were assessed by CAD, with a pathologic prediction rate of 98.1% (457 of 466). The NPVs of CAD for diminutive rectosigmoid adenomas were 96.4% (95% CI, 91.8% to 98.8%) (best-case scenario) and 93.7% (CI, 88.3% to 97.1%) (worst-case scenario) with stained mode and 96.5% (CI, 92.1% to 98.9%) (best-case scenario) and 95.2% (CI, 90.3% to 98.0%) (worst-case scenario) with NBI. Limitation Two thirds of the colonoscopies were conducted by experts who had each experienced more than 200 endocytoscopies; 186 polyps not assessed by CAD were excluded. Conclusion Real-time CAD can achieve the performance level required for a diagnose-and-leave strategy for diminutive, nonneoplastic rectosigmoid polyps. Primary funding source Japan Society for the Promotion of Science.

In July 2009, a 69-year-old man was admitted to our hospital because an abnormal chest shadow had been noted on medical examination. Chest radiography and computed tomography showed mediastinal and bilateral hilar lymphadenopathy. Bronchoalveolar lavage fluid (BALF) from the right B(5) revealed an increased CD4/CD8 ratio. Histological examination of the biopsy specimens obtained from the tumor in the left upper bronchus revealed small cell lung cancer, whereas examination of the specimens obtained from the left B(3) revealed noncaseating epithelioid cell granulomas containing giant cells, confirming the diagnosis of sarcoidosis. The patient underwent chemotherapy with carboplatin and etoposide without any steroids. After 4 courses of chemotherapy, bronchoscopic examination revealed that the tumor had shrunk, and the BALF CD4/CD8 ratio had decreased; further, no histological evidence of sarcoidosis was seen in specimens obtained from the left B(3). Concomitant small cell lung cancer and sarcoidosis is rare. Interestingly, cancer chemotherapy might improve pulmonary sarcoidosis.

Time-dependent characteristic changes of metal-insulator-metal (MIM) capacitors with HfAlO dielectric prepared by atomic-layer deposition under constant-voltage stress (CVS) were studied. It was found that relative dielectric constant , dielectric loss , temperature coefficient of capacitance , and frequency coefficient of capacitance gradually increase during CVS testing, whereas the voltage dependence of capacitance weakens. It was also found that changes in -value, , and during CVS testing linearly depend on changes in . These three linear relationships are basically explained by a dielectric-response model proposed for a ldquoflat-lossrdquo dielectric. That is, the increases in -value, , and are attributed to the dielectric-loss increase caused by voltage stress. Stress-time dependence of the dielectric-loss increase is expressed very well by a power function. That is, the power exponent obtained by a curve fitting linearly increases with stress voltage and decreases with increasing aluminum concentration in the HfAlO dielectric. This result indicates that aluminum addition into the HfAlO dielectric can improve the characteristic stabilities of a MIM capacitor under voltage stress.

To establish a method of measuring interconnect line-edge roughness (LER), low-k line patterns were observed and electric field concentration was simulated on the basis of observation results. Wedge-shaped LERs were observed at the edges of low-k lines, and the bottom and the top widths of the average wedge feature were 60 and 7 nm (or smaller), respectively. Simulation showed that LER causes serious electric field concentration, which may cause the degradation of time-dependent dielectric breakdown (TDDB) lifetime at 100-nm-pitch Cu/low-k interconnects. The maximum electric field strength depends on the conventional LER metric 3Rq, but depends more strongly on the wedge angle, the curvature of the tip. That is, other metrics such as wedge angle can predict fatal electric field concentration caused by LER than the conventional metric 3Rq.

Metal–insulator–metal (MIM) capacitors with Al2O3-laminated Ta2O5 insulators are fabricated and characterized in terms of voltage linearity and temperature linearity. Voltage dependence of capacitance in the laminated capacitor is dominated by the capacitance change in the Al2O3 layer. Therefore, the voltage-linearity coefficients of the laminated capacitor can be predicted using the coefficient of the single-layer Al2O3 capacitor and the effective oxide thickness (EOT) of the laminated capacitor. Moreover, the temperature coefficient of capacitance (TCC) is not dominated by an interface characteristic, but by a bulk characteristic of the insulators. We propose a model that the TCC of the laminated capacitor can be given by a linear combination of the TCC of each insulator and its EOT ratio. The model has been validated by experimental data.

This paper summarizes the latest developments regarding solid-state nanopores achieved in our laboratory. For direct DNA sequencing with solid-state nanopores, a simple method has been developed to precisely fabricate nanopores with diameters of 1 to 3 nm. By measuring DNA translocation events through the fabricated nanopores, it was confirmed that single-stranded DNA (ssDNA) can pass through nanopores with diameters as small as 1.2 nm. In addition, it was discovered that the translocation speed of ssDNA is higher than that for double-stranded DNA (dsDNA) by three or four orders of magnitude. This difference in speed was explained by a difference in the forces acting on the DNA. From molecular dynamics (MD) simulations, it was found that the force of solution-DNA interactions on dsDNA is approximately 10 times larger than that on ssDNA during DNA translocation through a nanopore.

DNA sequencing with a solid-state nanopore requires a reduction of the translocation speeds of single-stranded DNA (ssDNA) over 10 μs/base. In this study, we report that a nanometre-sized bead structure constructed around a nanopore can reduce the moving speed of ssDNA to 270 μs/base by adjusting the diameter of the bead and its surface chemical group. This decelerating effect originates from the strong interaction between ssDNA and the chemical group on the surface of the bead. This nanostructure was simply prepared by dip coating in which a substrate with a nanopore was immersed in a silica bead solution and then dried in an oven. As compared with conventional approaches, our novel method is less laborious, simpler to perform and more effective in reducing ssDNA translocation speed.

To improve the spatial resolution of solid-state nanopores, thinning the membrane is a very important issue. The most commonly used membrane material for solid-state nanopores is silicon nitride (Si3N4). However, until now, stable wafer-scale fabrication of Si3N4 membranes with a thickness of less than 5 nm has not been reported, although a further reduction in thickness is desired to improve spatial resolution. In the present study, to fabricate thinner Si3N4 membranes with a thickness of less than 5 nm in a wafer, a new fabrication process that employs a polycrystalline-Si (poly-Si) sacrificial layer was developed. This process enables the stable fabrication of Si3N4 membranes with thicknesses of 3 nm. Nanopores were fabricated in the membrane using a transmission electron microscope (TEM) beam. Based on the relationship between the ionic current through the nanopores and their diameter, the effective thickness of the nanopores was estimated to range from 0.6 to 2.2 nm. Moreover, DNA translocation through the nanopores was observed.

To achieve DNA sequencing using a solid-state nanopore, it is necessary to reduce the electric noise current. The noise current can be decreased by reducing the capacitance (C) of the nanopore device. However, we found that an electric-charge difference (ΔQ) between the electrolyte in one chamber and the electrolyte in another chamber occurred. For low capacitance devices, this electric-charge imbalance can lead to unexpectedly high voltage (ΔV = ΔQ/C) which disrupted the membrane when the two electrolytes were independently poured into the chambers. We elucidated the mechanism for the generation of initial defects and established new procedures for preventing the generation of defects by connecting an electric bypass between the chambers.

The barrier mechanism against copper-ion diffusion in silicon-oxide films deposited by plasma-enhanced chemical vapor deposition (PECVD) using trimethoxysilane (TMS) and nitrous oxide (N2O) chemistry (PE-TMS oxide) was studied. It was found that the flow ratio of TMS gas to N2O gas during deposition strongly affects a time-dependent dielectric-breakdown lifetime of PE-TMS oxide with a copper electrode as well as other PE-TMS oxide film properties such as electrical properties (leakage current and dielectric constant), a physical property (atomic composition), and chemical properties (chemical bonding states and wet-etching rate). The dielectric-breakdown lifetime of PE-TMS oxide film with a copper anode is a maximum at a source-gas ratio ranging from 1.7% to 3.3%. On the other hand, leakage current density, wet-etch rate, and dielectric-breakdown lifetime of PE-TMS oxide film with an aluminum electrode are degraded by increasing the source-gas flow ratio (0.83% to 12%). These results suggest that two type...

Reducing device capacitance is effective for decreasing current noise observed in a solid-state nanopore-based DNA sequencer. On the other hand, we have recently found that voltage stress causes pinhole-like defects in such low-capacitance devices. The origin of voltage stress, however, has not been determined. In this research, we identified that a dominant origin is static charge on the outer surface of a flow cell. Even though the outer surface was not in direct contact with electrolytes in the flow cell, the charge induces high voltage stress on a membrane according to the capacitance coupling ratio of the flow cell to the membrane.

Tomoya Harada, Akira Yamasaki, Takehito Fukushima, Kiyoshi Hashimoto, Miki Takata, Masahiro Kodani, Ryota Okazaki, Kenichi Takeda, Masanari Watanabe, Jun Kurai, Eiji Shimizu Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Japan Background: The administration of inhaled corticosteroids and worldwide usage of several asthma guidelines have improved asthma mortality. Elderly patients with asthma show high mortality rates, and may have several comorbidities, including overlap with chronic obstructive pulmonary disease (COPD). Among patients showing asthma overlapped with COPD (asthma–COPD overlap syndrome; ACOS), mortality is worse than for asthma alone. Therefore, we investigated comorbidities, malignancies, and causes of death in patients with asthma and ACOS. Methods: This was a retrospective study. From January 2000 to March 2012, 650 patients were followed up at Tottori University Hospital. Medical records were reviewed to collect data regarding patient characteristics and comorbidities, and causes of death were recorded for patients who died during the study period.Results: Eighty-seven patients died during the study period. The most frequent cause of death was malignancy. The proportion of malignant disease was 21.7% in all patients, 19.4% in patients with asthma alone, and 32.4% in patients with ACOS. One patient died from an asthma attack during this period.Conclusion: The most frequent cause of death in patients with asthma and ACOS was malignant disease. It is necessary to control not only asthma but also comorbidities in patients with asthma, especially in those with ACOS. Keywords: asthma, chronic obstructive pulmonary disease, asthma-COPD overlap syndrome, mortality

Chapter 9 introduces the results of Japanese national research and development (R&D) initiative of 3D integration technology using through-silicon via (TSV) over the 5-year period from 2008 to 2012. Association of Super-Advanced Electronics Technologies (ASET) conducted the “Development on Functionally Innovative 3D-Integrated Circuit (Dream Chip) Technology Project,” and it was managed by the NEDO organization. The development subjects consisted of thermal management/chip-stacking technology, thin wafer technology, and 3D integration technology, ultrawide bus 3D-SiP, mixed signal (digital -analog) 3D, and heterogeneous 3D technology.

The room-temperature reaction between copper (Cu) and silicon (Si) was investigated. The areas of an Si substrate covered with very thin or island-like Cu oxidized formed thick (>100 nm) oxide (SiO2). The areas covered with thick and nonisland-like Cu film did not. These unoxidized areas transformed into SiO2 when the side surfaces of the sample were exposed to air after sectioning for transmission electron microscope observation. The supply of oxygen was found to control this oxidation process. The presence of a Cu silicide, such as Cu3Si, was found to not necessarily be needed for oxidation. The oxidation rate estimated from observation was about 150 nm/month. Copper atoms were detected at the SiO2/Si interface and identified not as silicides but as body-center-cubic-structured Cu several atom layers thick.