Search

Liquid biopsies such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have great potential to serve as prognostic and predictive biomarkers in urologic cancers. The possibility of using liquid biopsies for real-time noninvasive and dynamic monitoring of response to therapy has been an active area of investigation. In this brief review, we outline the evidence for the potential clinical utility of CTC and ctDNA analyses in prostate, urothelial, and renal cancers.

Muscle-invasive bladder cancer can be treated with either radical cystectomy or bladder preservation approaches, and there is a need for reliable biomarkers to guide the optimal choice of therapy. The recent elucidation of the genomic landscape and biological drivers of bladder cancer has enabled the identification of tumor molecular features that may be helpful in driving clinical decision-making. Here, we summarize recent efforts to develop molecular biomarkers that could be leveraged to guide therapeutic decisions, post-treatment monitoring, and the optimal use of bladder preservation approaches for the effective treatment of muscle-invasive bladder cancer.

Background Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. Objective To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. Design, setting, and participants We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5 yr, and median follow-up time for patients without an event was 5.0 yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Outcome measurements and statistical analysis Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Results and limitations Gene expression profiling of TMT cases identified luminal (N = 40), luminal-infiltrated (N = 26), basal (N = 54), and claudin-low (N = 16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p = 0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p = 0.006), but not in the TMT cohort. This study is limited by its retrospective nature. Conclusions Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. Patient summary We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.

PURPOSE/OBJECTIVE(S) To evaluate a convolutional neural network auto-contouring (AC) model created for treatment planning in patients receiving radiotherapy for localized prostate cancer after insertion of a radiopaque rectal spacer hydrogel. MATERIALS/METHODS The deep learning model, trained by 125 patients, auto contours target volumes (prostate and proximal seminal vesicles), OARs (bladder, rectum, femoral heads and penile bulb) and radiopaque rectal spacers. ACs were evaluated against MD manual contours (MCs) submitted for treatment planning. ACs were not available for MD review while creating MCs. Individual volumes as well as composite volumes (overall performance) were qualitatively evaluated by a radiation oncologist using a 1 (minor discrepancy, little to no dose-volume impact), 2 (moderate discrepancy or editable with substantial efficiency gain), 3 (significant discrepancy or editable with meaningful efficiency gain), and 4 (rejected due to gross error or editable without efficiency gain) scoring scale. Quantitative evaluation of geometric differences was performed with mean distance to agreement (MDA) and Dice Similarity Coefficient (DSC) for each volume. RESULTS A total of 68 cases were evaluated by quantitative and qualitative metrics (Table 1). MCs were performed by 4 experienced MDs. Average composite score of 2.22 (SD 0.73) indicates substantial to meaningful efficiency gain in contouring process. Composite scores for 100% of cases evaluated indicate a meaningful efficiency gain in the contouring process, with 60% of composite scores indicating only minor to moderate discrepancy between contours. Prostate and SV AC average scores were above 2. Mean prostate MDA and DSC were 1.71 and 0.85, respectively, both within tolerance range recommended by AAPM TG 132. CONCLUSION The model can accurately auto contour target volumes, OARs and spacer with meaningful to substantial efficiency gain, with a majority of target volumes qualitatively evaluated by a physician as having only mild to moderate discrepancies. Quantitative analysis shows contours for most OARs have only minor geometric differences unlikely to have significant dose-volume impacts. Further analysis with comparison of treatment plans generated from ACs and MCs is warranted.

Summary Although muscle-invasive bladder cancer is commonly treated with radical cystectomy, a standard alternative is bladder preservation therapy, consisting of maximum transurethral bladder tumour resection followed by radiotherapy with concurrent chemotherapy. Although no successfully completed randomised comparisons are available, the two treatment paradigms seem to have similar long-term outcomes; however, clinicopathologic parameters can be insufficient to provide clear guidance in the selection of one treatment over the other. Recent advances in the molecular understanding of bladder cancer have led to the identification of new predictive biomarkers that ultimately might help guide the tailored selection of therapy on the basis of the intrinsic biology of the tumour. In this Review, we discuss the existing evidence for molecular alterations and genomic signatures as prognostic or predictive biomarkers for bladder preservation therapy. If validated in prospective clinical trials, such biomarkers could enable the identification of subgroups of patients who are more likely to benefit from one treatment over another, and guide the use of combination therapies that include other modalities, such as immunotherapy, which might act synergistically with radiotherapy.

Introdução: A escassez de insumos tem sido uma grande limitação para o avanço da vacinação. O objetivo deste estudo foi avaliar a efetividade, imunogenicidade e segurança da meia dose da ChAdOx1 nCoV-19. Métodos: Ensaio clínico controlado não randomizado de fase III com grupos de comparação interna e externa (profissionais de saúde vacinados com dose plena). Moradores de Viana-ES, 18-49 anos, receberam duas meias doses da ChAdOx1 nCoV-19, com intervalo de 8 semanas. Foram estudados a incidência novos casos, número de mortes, internações e admissões em UTI, anticorpos neutralizantes por teste de neutralização em placa (PRNT) e quimioluminescência contra a porção RBD da fração S1 da proteína Spike, anticorpos totais IgG específico para SARS-Cov2, fatores solúveis sistêmicos, imunidade celular por estimulação antígeno-específica de células mononucleares do sangue periférico in vitro e investigação de Linfócitos T e B de memória e de citocinas intracitoplasmáticas. Eventos adversos foram monitorizados por diário, registro em plataforma digital, busca ativa por telefone, notificações no E-SUS notifica. Tempos de coleta: antes, 28 dias após 1ª.(D1) e 2ª. (D2) doses, e seguimento 3,6,12 meses pós D2. Resultados: Dos 27.000 elegíveis, 20.546 indivíduos receberam duas meias doses. Desses, 572 coletaram amostras biológicas. Após D2, a taxa de soroconversão entre soronegativos no baseline (n = 239) foi 99,8% semelhante à dose plena (DP) (n = 104, 100%). A média geométrica dos títulos de anticorpos (IC95%; UA/dL) foi 1.324 (1.148-1.527) com a MD e 3.727 (2.975-4.668) com DP (p < 0,001). No subgrupo com infecção natural prévia, os títulos foram semelhantes à dose padrão, mas houve queda dos títulos após D2 comparado com D1 nos dois grupos (MD = 9.569 (8.768-10.443) vs. 5.742 (3.195-6.347)), (DP = 9.533 (7.377-12.319) vs. 4.915 (3.767-6.412)). A frequência de eventos adversos foi semelhante, mas a duração dos sintomas foi menor no grupo MD. Não ocorreram eventos adversos graves. Taxas de casos confirmados após imunização completa foi semelhante à dose plena (20/248.830 vs. 28/419.248 casos/pessoas dia). Conclusão: Meia dose da ChAdOx1 nCoV-19 é segura, imunogênica e capaz de induzir anticorpos neutralizantes em 99,8%. Em pessoas que tiveram infecção natural, uma meia dose foi semelhante a dose plena, e suficiente para induzir altos títulos de anticorpos. Resultados de imunidade celular e efetividade estão sendo analisados. Apoio: ICEPi/SESA, MS, PNI, OPAS, HUCAM, UFES, EBSERH.

Advances in our molecular understanding of cancer biology have paved the way to an expanding compendium of molecularly-targeted therapies, accompanied by the urgent need for biomarkers that enable the precise selection of the most appropriate therapies for individual cancer patients. Circulating biomarkers such as circulating tumor cells (CTCs) are poised to fill this need, since they are "liquid biopsies" that can be performed non-invasively and serially, and may capture the spectrum of spatial and temporal tumor heterogeneity better than conventional tissue biopsies. Increasing evidence suggests that moving beyond the enumeration of CTCs towards more sophisticated molecular analyses can provide actionable data that may predict and potentially improve clinical outcomes. In this review, we discuss the potential of molecular CTC analyses to serve as prognostic and predictive biomarkers to guide cancer therapy and early cancer detection. As technologies to capture and analyze CTCs continue to increase in sophistication, we anticipate that the potential clinical applications of CTCs will grow exponentially in the coming years.

Purpose/objective(s) Radiotherapy (RT) with or without androgen deprivation therapy (ADT) plays a key role in the salvage treatment of prostate cancer recurrent after prostatectomy. However, not all patients benefit from salvage therapy, and there is an unmet need for biomarkers to distinguish responders from non-responders. Prostate cancer depends on androgen receptor (AR) signaling, and expression of AR splice variants (ARVs) that enable androgen-independent AR signaling is associated with resistance to ADT in the metastatic setting. Recent in vitro data suggest that ARVs also mediate DNA repair after irradiation, suggesting that ARV expression may also be a biomarker of resistance to RT. However, the landscape of ARV expression in primary prostate cancer and its effect on treatment outcomes remain unexplored. Here, we hypothesized that ARVs may be detectable in primary prostate cancer and furthermore may modulate response to salvage RT+ADT. Materials/methods We retrospectively identified 46 prostate cancer patients treated with prostatectomy followed by salvage RT+ ADT at a single institution from 1995 to 2012. Median age at salvage was 64.5 years. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. We comprehensively interrogated the landscape of ARVs by performing ultra-deep targeted RNA-seq of archival formalin-fixed paraffin-embedded prostatectomy samples. Using a custom library of > 3000 primers spanning all AR exons and introns, we evaluated 21 native splice junction sites and 20 splice variants with a mean depth of coverage of > 5000x. We tested for association between splice variant expression and clinical outcomes using the log-rank test and Cox proportional hazards model. Results In total, 76% of patients had one or more detectable AR splice variants. The most commonly detected variants were AR-45 (exon 1b-2) in 41%, AR-V9 (exon 3-cryptic exon (CE) 5) in 20%, and AR-V7 (exon 3-CE3) in 13%. At a median follow-up of 33.8 months, biochemical progression-free survival (BPFS) at 3 years was 60%, distant metastasis-free survival was 90%, and overall survival was 100%. Among detected splice variants, only AR-V7 was associated with differential clinical outcomes, with a median BPFS of 10.9 months in AR-V7 positive vs 73.4 months in AR-V7 negative patients (P = 0.0020, HR 5.23, 95% CI 1.62-16.87). Conclusion Using a custom ultra-deep targeted RNA-Seq approach, we provide among the first comprehensive descriptions of the AR splice variant landscape in primary prostate cancer. Moreover, we show that detectable AR-V7 expression in prostatectomy specimens was associated with inferior outcomes following subsequent salvage RT+ADT, suggesting for the first time that AR-V7 may modulate outcomes for localized as well as metastatic disease.

Purpose Prevention of air introduction during mechanical circulatory support device implant is critical for a successful outcome. A substantial amount of air may be introduced into the circulation during pump to outflow port connection, which may become detrimental for optimal pump function and long-term survival. In this study, we evaluated techniques of seamless, airless connection of double-ended centrifugal pump (continuous-flow total artificial heart [CFTAH]) in vivo. Methods The airless CFTAH connection techniques were evaluated in acute in vivo (n=2) CFTAH implants (Jersey calves, weight: 77.8 and 80.8 kg). Techniques consisted of pump priming with normal saline (Fig. 1 A) and application of specifically designed connection sleeve (Fig 1B). The silicone sleeve (0.3-0.5 mm thick) was prototyped using multilayer dip-coating technique over a 3D-printed mandrel. A suture line was added along the long axis, to enable easy removal. Deairing sleeve was pre-placed on each outflow port (conduit) and proximal port (port) ends (Fig.1 C). The present air was evacuated upward from an open line. The conduit and pump ports were connected within the sleeve (Fig.1 D), with air being fully excluded from circuit. The CFTAH was started at the minimum speed (2,200 rpm) after connection. Results The CFTAH pump were successfully primed with saline prior to implant to remove entrapped air. The completely seamless pump connection and exclusion of air from pump and outflow grafts has been found feasible. There were no clinical signs of air embolism in the pulmonary or systemic circulation observed during the experiment. Conclusion The seamless connection of CFTAH to outflow grafts using specifically designed connection sleeve and its easy removal was demonstrated to be feasible. Device development is ongoing and will aim to address optimal geometry, size and material selection.

The recent expansion of therapeutic options for the treatment of metastatic prostate cancer highlights the need for precision medicine approaches to enable the rational selection of appropriate therapies for individual patients. In this context, circulating biomarkers in the peripheral blood are attractive as readily accessible tools for predicting and monitoring therapeutic response. In the case of circulating tumor cells and circulating tumor DNA, they may also serve as a noninvasive means of assessing molecular aberrations in tumors at multiple time points before and during therapy. These so-called "liquid biopsies" can provide a snapshot view of tumor molecular architecture and may enable clinicians to monitor the molecular status of tumors as they evolve during treatment, thus allowing for individualized precision therapeutic decisions for patients over time. In this review, we outline recent progress in the field of circulating biomarkers in metastatic prostate cancer and evaluate their potential for enabling this vision of real-time precision medicine.

Purpose The latest version of the continuous flow total artificial heart (CFTAH), which incorporates a novel stacked motor to improve passive self-regulation of pressure difference between the left and right atria, and reduce pump rotor over-excursion, was tested in vivo in a calf model to assess operational performance. Methods The CFTAH was implanted in a calf and run at various pump operating conditions including mean pump speeds from 2400 to 3600 RPM, sinusoidal speed modulations from 0 to 25%, and speed modulation rates from 80 to 120 B.M. It was also tested under various combinations of simulated high and low systemic vascular resistance and pulmonary vascular resistance via outlet graft clamping and administration of a Nitroprusside respectively. Results The CFTAH responded to all control inputs and ran as expected during the experiment. The head curves of the right and left pumps generated from measured pressures, measured right flow and calculated left flow, were consistent with in vitro data on this pump. The passive atrial pressure regulation performed well in the normal operating range, and there were no signs of excessive rotor axial displacement during extreme pressure excursions as had been seen in the previous versions of the pump. The left atrial pressure was unusually low throughout most of the experiment and we believe that this may have been due to partial blockage of the of the left inflow cuff proximal to the pressure line tap. This led to several left inlet suction conditions and extreme pressure conditions. Conclusion The replacement of the standard, single stack stator motor with the new dual stator stack motor resulted in better passive regulation of the pressure difference between the left and right atria. Also, the extreme pressure conditions resulting from left inlet suction events did not cause the pump's rotor to rub against the volute housing as had been seen in previous versions of the pump. Even though the self-regulation was acceptable, shifting of the regulation characteristic to increase the nominal LAP-RAP value will improve the regulation further, and this modification will be implemented prior to the next in vivo experiment.

Purpose In patients with severe biventricular heart failure (HF) and cardiogenic shock, use of biventricular assist device (BVAD) can be a treatment of choice. We are developing an advanced ventricular assist device (AVAD) intended to serve as universal pump for left and/or right heart failure (Fig.1 A,B). The purpose of this initial in silico simulation study was to demonstrate that AVAD design can be suitable for biventricular support. Methods The virtual mock loop (VML) was developed (MATLAB; MathWorks®) to simulate hemodynamic parameters as they surge through the BVAD-supported systolic HF cardiovascular system. The AVAD used as in BVAD configuration was in 2 speeds (3400 rpm left, 2000 rpm right) to get comparable systemic flow and pressure outputs. LVAD support was adjusted to maintain 5.0 L/min total systemic flow. For BVAD, the added RVAD support was adjusted to maintain left and right atrial pressure (LAP-RAP) at 3-5 mm Hg. Results The BVAD performance was maintained very well for both left ventricular (L-AVAD) and right ventricular (R-AVAD) support within specified speed range (Fig1 C,D). L- AVAD speed of 3000 - 3500 rpm provided sufficient support for the case of severe left and right systolic heart failure, assuming there was no aortic valve regurgitation. At the simulated condition, with L-AVAD support, the aortic valve remains closed and the systemic pressure has reduced pulse. A stable hemodynamics were maintained. The atrial pressure difference (LAP-RAP) resulted to be sensitive to the right pump speed, though was balanced whenever there was any positive flow through the pulmonary valve. Introduction of R-AVAD support to the L-AVAD support caused the left atrial pressure to increase resulting in increased filling of the left ventricle and a corresponding increase in aortic pulsatility. Conclusion These initial in silico study demonstrated that use of the universal AVAD as BVAD supports cardiac output and arterial pressure in biventricular HF condition.

Effect of Si content on microstructures, tensile properties, and creep properties in a gravity-cast Mg–6Al-0.4Mn–2Ca (wt.%, AMX6042) alloy has been investigated. High content of Si addition increases the ductility of the AMX6042 alloy without large loss of strengths; however, addition of Si over 0.6 wt.% decreases fraction of (Mg,Al)2Ca phases significantly. Moreover, such high content of Si promotes formation of Mg17Al12 phases, leading to poor creep properties. Although addition of Si tends to decrease fraction of (Mg,Al)2Ca phases and promote formation of Mg17Al12 phases, good creep properties could be kept up to 0.47 wt.% Si addition.

The thermal transformations and crystal structures in the ordered bcc phases appearing in Ni 2− x MnSb alloys have been investigated. Thermo-analyses on NiMnSb( x = 1) show three λ-shaped peaks suggesting a magnetic and chemical ordering transitions at approximately 450, 865 and 965 °C. With decreasing x , the first and second peak temperatures gradually decrease, while the third one increases. By Z- contrast imaging technique, it was confirmed that the second peak corresponds to the order-disorder transition of vacancies from the L 2 1 to the C 1 b structure.

Neurobiological and genetic mechanisms underlying increased intake of and preference for nutritive sugars over non-nutritive sweeteners are not fully understood. We examined the roles of subnuclei of the amygdala in the shift in preference for a nutritive sugar. Food-deprived mice alternately received caloric sucrose (1.0 M) on odd-numbered training days and a non-caloric artificial sweetener (2.5 mM saccharin) on even-numbered training days. During training, mice with sham lesions of the basolateral (BLA) or central (CeA) nucleus of the amygdala increased their intake of 1.0 M sucrose, but not saccharin. Trained mice with sham lesions showed a significant shift in preference toward less concentrated sucrose (0.075 M) over the saccharin in a two-bottle choice test, although the mice showed an equivalent preference for these sweeteners before training. No increased intake of or preference for sucrose before and after the alternating training was observed in non-food-deprived mice. Excitotoxic lesions centered in the BLA impaired the increase in 1.0M sucrose intake and shift in preference toward 0.075 M sucrose over saccharin. Microlesions with iontophoretic excitotoxin injections into the CeA did not block the training-dependent changes. These results suggest that food-deprived animals selectively shift their preference for a caloric sugar over a non-caloric sweetener through the alternate consumption of caloric and non-caloric sweet substances. The present data also suggest that the BLA, but not CeA, plays a role in the selective shift in sweetener preference.

SummaryCirculating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they greatly contribute to the metastatic spread of cancer.

The concentration of parathyroid hormone-related protein (PTHrP) in the blood of healthy animals is extremely low. However, milk contains a relatively large amount of PTHrP, and the changes in its levels in the early stages of lactation in cows remain unclear. To understand the characteristics of parturient changes in milk PTHrP content and the biological implications thereof, changes in milk PTHrP concentrations were measured at 7 time intervals between parturition and 21 days postpartum in 8 primiparous and 8 multiparous Holstein cows. Based on these results, milk samples were collected from 47 primiparous and 66 multiparous Holstein cows at 3 days postpartum to investigate the relationship between milk PTHrP concentration and the variables of cow age, milk yield, and milk calcium concentration. Milk PTHrP concentration in both parity groups was found to be lowest on the day of parturition (primiparous, 3.1±0.5 nM and multiparous, 1.6±0.3 nM) but to significantly increase on day 14 of lactation in primiparous cows (6.2±0.8 nM) and day 7 of lactation in multiparous cows (4.1±0.2 nM). Comparison of the 2 groups revealed that milk PTHrP concentrations in primiparous cows were higher than those of multiparous cows in the first 3 days of lactation. Although a significant negative relationship was found between milk PTHrP concentration and both age ( r =−0.65) and milk calcium concentration ( r =−0.19) at 3 days postpartum, no significant correlation was found between milk PTHrP concentration and milk yield. The study thus identified 3 unique characteristics of milk PTHrP concentration in the early stages of lactation: milk PTHrP concentration is higher in primiparous than multiparous cows, milk PTHrP concentration is lower in colostrum than later milk, and the difference in milk PTHrP concentration between primiparous and multiparous cows at 3 days postpartum is more strongly influenced by age than milk yield.

Purpose Biventricular assist device (BVAD) implantation is the treatment of choice in patients with severe biventricular heart failure (BHF) and cardiogenic shock . We previously developed a miniaturized continuous flow double-ended centrifugal pump intended for total artificial heart implant (CFTAH). The purpose of this initial in vitro study was to prove that scaled down CFTAH can be suitable for biventricular support. Methods The CFTAH was tested in BVAD configuration at 2 pump speeds (4500 and 6000 rpm) on a pulsatile mock loop with two pneumatic ventricles that simulated normal and heart failure conditions (moderate and severe) by adjusting the systolic and diastolic drive pressures to simulate hemodynamics of the failing biventricular function. Results The BVAD performance was maintained very well for both atrial and ventricular cannulation within the 4500 - 6000 rpm range. A stable hemodynamics were maintained, and the pump's self-regulating performance was confirmed with the most of atrial pressure difference (LAP-RAP) falling within ±5-15 mm Hg in (Mod.) and severe (Sev.) right (RHF) and left HF (LHF) conditions. Left and right pump flows (LPF and RPF) and total flow (TF) increased as the BVAD speed was increased (Figure). The TF was higher than LPF and RPF due to output from the native ventricles, and the LPF was higher than RPF with pump speed of 6,000 rpm, but the TF appeared balanced due to larger native right ventricular output vs. native left ventricle with given condition. Conclusion These initial in vitro study demonstrated that use of the CFTAH as BVAD supports cardiac output and arterial pressure in BHF conditions. In vivo evaluation of this technology is currently pending.

Purpose The aim of this study was to assess a new pump's performance and function by using a virtual mock loop (VML) system for device characterization and mapping. Methods We are developing a novel miniaturized left ventricle assist device (LVAD) configured for transapical insertion (Perfusions Solutions Inc., South Euclid, OH). The results of pump testing in the laboratory, such as pressure-flow performance curves, were used for the analysis of its function as an LVAD. The VML system was programmed to mimic various types of heart failure and provide hemodynamic pressure values before and after activation of LVAD. The circulatory conditions of the VML system were systolic heart failure (SHF), diastolic HF (DHF), and both systolic and diastolic HF (BHF). Results Before and after pump activation with SHF condition and with a pump speed of 14000 RPM, aortic pressure (AoP) increased from 71/50 to 99/97 mm Hg, pulmonary artery pressure (PAP) changed from 44/36 to 44/33 mm Hg, mean left atrium pressure (mLAP) decreased from 25 to 18 mm Hg, mean right atrium pressure (mRAP) increased from 7 to 10 mm Hg; with DHF, AoP changed from 116/81 to 129/113 mm Hg, PAP was 45/34 to 45/31 mm Hg, mLAP was 18 to 15 mm Hg, mRAP was 10 to 12 mm Hg; with BHF, AoP was 65/46 to 98/96 mm Hg, PAP was 44/36 to 45/33 mm Hg, mLAP was 26 to 19 mm Hg, mRAP was 7 to 10 mm Hg. (Figure A; pressure-volume curve with BHF, B; pressure curve with BHF without LVAD, 14000 RPM and 16000 RPM of the pump speed) Conclusion Due to the test results from the VML system, the new LVAD for transapical insertion could have the ability enough to ease symptoms of the patients with various types of heart failure based on results from VML system.

Purpose Heart transplantation in infants and children is an accepted therapy for congenital heart disease, but donor organ availability remains unstable. Mechanical circulatory support is another standard option, but there is a lack of implantable devices due to size and functional range. The purpose of this study was to evaluate in vivo performance of the initial prototype of an infant continuous-flow total artificial heart (I-CFTAH) with one motor and one rotating assembly supported by a hydrodynamic bearing. Methods The I-CFTAH was designed to cover a range of 3 kg infant to 9 kg child (flange diameter - 26.9 mm; length - 44 mm), with nominal design point was matched to a 6 kg child, requiring 1.0 L/min of flow. I-CFTAH was tested using in silico virtual simulation mock loop (VML; MATLAB; MathWorks®) and simulated the hemodynamics as they surge through the system implanted with blood pump (run at 0.5 L/min for 3 kg infant). Lumped-parameter model including systemic/pulmonary circulation, values for impedance, beat rate, and blood volume was used. Results The in silico experiments showed intended performance of scaled down pump (left and right pump flows - 0.5 L/min at 4380 RPM). The difference between the left and right atrial pressures was maintained within ± 5-15 mm Hg. Simulation of I-CFTAH was successfully performed and allowed creating arterial pulsation with this device. Conclusion The present simulation-based approach showed feasibility of I-CFTAH design. The I-CFTAH met the proposed requirements for self-regulation, performance and pulse modulation. Further in vitro validation and in vivo implantation will be necessary to explore this technology in more detail.

Many patients with heart failure have preserved ejection fraction but also diastolic dysfunction, with no effective therapy. We are developing a new pump (Left Atrial Assist Device, LAAD) implanted at the mitral position to pump blood from the left atrium to fill the left ventricle properly. The

The SCRIT electron scattering facility, aiming at electron scattering off short-lived unstable nuclei, has been constructed at the RIKEN RI Beam Factory. This facility consists of a racetrack microtron (RTM), an electron storage ring (SR2) equipped with the SCRIT system, and a low-energy RI separator (ERIS). SCRIT (self-confining radioactive isotope ion targeting) is a novel technique to form internal targets in an electron storage ring. Experiments for evaluating performance of the SCRIT system have been carried out using the stable 133Cs1+ beam and the 132Xe1+ beam supplied from ERIS. Target ions were successfully trapped in the SCRIT system with 90% efficiency at a 250 mA electron beam current, and luminosity exceeding 10 26 /(cm2 s) was maintained for more than 1 s. Electrons elastically scattered from the target ions were successfully measured. Applicability of the SCRIT system to electron scattering for unstable nuclei has been established in experiments.

A method to evaluate regional stress state and Young’s modulus by analyzing the mining-induced deformation of ground is proposed. The effect of changes in regional strain state due to tectonic plate motion can be accounted for using the proposed method. Mining-induced deformation can manifest itself as changes in ground surface geometry resulting from mining activity. There are three underlying factors that can contribute to the deformation, these being: displacement induced by the effect of gravity; displacement induced by the effect of horizontal regional strain; and, incremental change in the horizontal regional strain. Both regional strain and Young’s modulus can be simultaneously estimated, because the displacement induced by the regional strain is independent of the Young’s modulus and the displacement induced by the gravity is inversely proportional to the Young’s modulus. The relative displacement arising from the mining excavation at the Torigatayama limestone mine in Japan has been measured by GPS. Both the regional stress state and Young’s modulus were estimated by back analysis of the relative displacement using a 3-D finite element method. It was shown that back analysis based on changes in distance between the measurement points provides a more reliable estimation than that could be achieved based on the direct relative displacement.

Phase equilibria at 700 and 850 °C, critical temperatures of B 2/ L 2 1 order–disorder transformation and martensitic and ferromagnetic phase regions at room temperature in the Ni–Mn–In system were determined mainly by diffusion triple method using a two-stage diffusion couple technique. It was confirmed that a single phase region of the β phase at both 700 and 850 °C exists in a wide composition range along the NiMn–NiIn section and that the L 2 1 ordered phase region appears in the vicinity of Ni 2 MnIn in the temperature region below about 800 °C. The composition lines, iso- M s and iso- T FM , possessing the M s and T C temperatures at room temperature, respectively, were successfully estimated and the coincidence between the iso- M s and iso- T FM was confirmed in the composition region from 10 to 20 at.% In in the β-phase region.

The order–disorder transformation and the magnetic properties of Heusler-type Ni50Mn50−xInx ternary alloys were investigated. The B2/L21 order–disorder transformation temperatures are detected at about 800–1100 K. In the alloys with the L21 structure, while the spontaneous magnetization at 4.2 K monotonically decreases with increasing x, the Curie temperature is almost constant with x ⩽ 25 and decreases linearly with x > 25. This unique behavior is qualitatively explained by the concept of local magnetic moment of Mn atoms.

Whereas acute pneumocephalus has been well characterized in the literature: typically seen postoperatively after neurosurgical and neurotological procedures, a chronic pneumocele developing several years after surgery is highly unusual. Most otogenic pneumocephali develop in an acute or subacute fashion, presenting with focal neurological symptoms, headache or signs of meningitis secondary to translocation of bacteria into the cavity. We describe a patient with a supra-auricular soft-tissue swelling as the only presenting symptom of a large chronic epidural pneumocele with extension into the extracranial subcutaneous tissues. It presented several years after surgical resection of a meningioma that involved the temporal bone.

Ductile fracture behavior of a 5052 aluminum alloy sheet undergoing cyclic plastic deformation is investigated in order to clarify the effect of cyclic plastic deformation on formability enhancement in incremental stretch sheet forming at room temperature. In the incremental forming, formability markedly increases owing to strain distribution and accumulation effects. The former effect is activated when the deformation region expands along tool paths. Thus, localization of deformation, which leads to necking or fracturing, can be prevented. On the other hand, local strain is accumulated without fracturing when a blank sheet is repeatedly subjected to out-of-plane deformation at the same position. In this paper, the effect of the strain accumulation due to cyclic deformation generated by bending and unbending is primarily focused on to discuss the effect on deformability. To apply cyclic plastic straining to the specimen, a cyclic stretch-bending test was adopted. A cyclic tensile test was also conducted for larger bending curvature. The experimental results show that cyclic bending–unbending affects the ductility of sheet metals. The fractography obtained by scanning electric microscopy also indicates that fewer and smaller voids are observed particularly on bending the inner side than on the outer side.

Profound sensorineural hearing loss secondary to cochlear dysplasia presents a number of surgical challenges during cochlear implantation. The standard transmastoid-facial recess approach can be performed in the majority of cases. In cases of common cavity deformity, the transmastoid labyrinthotomy approach has a number of advantages. A high incidence of CSF gushers occurs in this population but can be managed by creating a small cochleostomy and tightly sealing the cochleostomy with connective tissue. Acceptable postoperative speech perception results can be expected.

We investigated relations between sustained visual attention, behavioral inhibition skills, and speech–language outcomes in prelingually deaf children who use cochlear implants (CIs) using two computerized continuous performance tasks (CPTs). One test measured their ability to sustain visual attention to a string of numbers and another test measured their ability to delay a behavioral response. Performance on latter task was related to postimplant scores on tests of vocabulary knowledge, language skills, and speech intelligibility. We conclude that behavioral inhibition skills of prelingually deaf children are related to several audiological outcome measures in deaf children with CIs. Our findings suggest that further investigation is warranted into executive functions and subvocal rehearsal skills of deaf children with CIs.

The c-axis oriented YBa 2 Cu 3 O 7-δ (Y123) bulk superconductors with up to 2.0 wt.% CeO 2 and 18 mm in diameter were prepared by the so-called MMTG process. The critical current density J C significantly increased with 1.0 or above wt.% CeO 2 additions. The sample with 2.0 wt.% CeO 2 additions exhibited a J C of 330,000 A/cm 2 at 35 K and 0 T, when the field was applied parallel to the c-axis of the sample. The maximum of the trapped magnetic field reached 4.2 T at 30 K at the center of the sample surface, which is more than 10 times larger than conventional Nd-Fe-B permanent magnets. Particles of a Ce-Ba compound, whose existence was identified from the observations using a scanning electron microscope, are not distributed uniformly in the Y123 matrix. This high trapped magnetic field of the sample with 2.0 wt.% CeO 2 additions can be explained in terms of a more homogeneous distribution of fine Y 2 BaCuO 5 (Y211) particles in the Y123 matrix compared with the CeO 2 -free sample.

To clarify the scaling law of fine scale eddies in turbulent channel flows, direct numerical simulations are conducted for Re τ =180, 400 and 800. The diameter and the maximum azimuthal velocity of coherent fine scale eddies can be scaled by Kolmogorov microscale ( η ) and Kolmogorov velocity ( u k ). The most expected diameter and maximum azimuthal velocity are 8–10 η and 1.2–2.0 u k , respectively. Near the wall, the most expected diameter increases to 10 η from 8 η and the most expected maximum azimuthal velocity increases to 2.0 u k from 1.2 u k . Strain rates at the center of the coherent fine scale eddies are small compared with the mean strain rate of the whole flow field. The strain rates acting on the fine scale eddies away from the wall coincide with those in homogeneous isotropic turbulence and turbulent mixing layer. However, relatively large strain rates are acting on the near-wall coherent fine scale eddies. The most expected angle between the intermediate eigenvector and the rotating axis of the fine scale eddy is about 15–17°, which is independent of the turbulent flow fields. The probability that coherent fine scale eddies exist in low-speed streaks is higher than that in high-speed streaks. Large scale structures of wall turbulence are visualized by showing spatial distributions of central axes of coherent fine scale eddies.

We have performed a study to optimize the measurement conditions for SIMS analysis of thin HfSiON films with various nitrogen concentrations, prepared by post-nitridation of HfSiO x . In this study of 2.5 nm thick HfSiON films, we have measured SIMS depth profiles of oxygen and nitrogen under 500 eV Cs + bombardment at approximately 70° from the surface normal, similar to those obtained by HR-RBS. Under the same measurement conditions, good correlation between the estimated nitrogen concentration from XPS and the CsN + secondary ion intensity by SIMS has been observed for nitrogen concentrations less than 15%.